Methods and compositions for sustained delivery of drugs

ABSTRACT

The present disclosure relates to methods and compositions for the topical sustained delivery of therapeutic agents. Topical application of compositions containing a muscle fasciculating agent result in the sustained release of any therapeutic agent contained within the composition. More particularly, topical application of such compositions to the outer surface of the eyelid of a patient results in increased absorption and sustained release of the therapeutic agent into the eyes or systemically.

CROSS-REFERENCE OF RELATED APPLICATION

This application claims priority to provisional application, U.S.Application No. 61/256,614, filed Oct. 30, 2009 and U.S. ApplicationSer. No. 61/289,471, filed Dec. 23, 2009, both of which are incorporatedherein by reference thereto.

TECHNICAL FIELD

The present invention relates generally to methods and compositions forthe controlled topical delivery of drugs. More specifically, the presentinvention relates to methods and compositions for delivery of one ormore drugs to the eye, a specified area of the eye or systemically to aremote target by topical application to at least one upper eyelid andoptionally at least one lower eyelid. More specifically, these methodscomprise applying a preparation containing the desired drug orcombination of drugs to the surface of at least one upper eyelid andoptionally at least one lower eyelid, thereby causing transfer of thedrug or drugs from the eyelid into the eye or systemic circulation viathe vascular network within the eyelid.

BACKGROUND OF THE INVENTION

The treatment of human illness may be accomplished by administeringdrugs to the human body via various routes, e.g., oral, sublingual,rectal, parenteral, topical, inhalation, etc. The main advantage oftopical delivery of drugs is convenience, with the added benefits thatthis delivery route avoids bypass metabolism, the risks andinconveniences of intravenous therapy and varied absorption rates and/orgastric emptying times. Topical delivery is generally defined as theapplication of a drug-containing formulation to the skin to directlytreat cutaneous disorders, e.g., acne or the cutaneous manifestations ofa general disease, e.g., psoriasis with the intent of containing thepharmacological or other effect of the drug to the surface of the skinor within the skin. Semi-solid formulations in all their diversitydominate the system for topical delivery, but foams, spray, medicatedpowders, solution, and even medicated adhesive systems are in use.

Topical delivery includes two basic types of product: (1) externaltopicals that are spread, sprayed, or otherwise dispersed on tocutaneous tissues to cover the affected area and (2) internal topicalsthat are applied to the mucous membrane orally, vaginally or onanorectal tissues for local activity. For the most part topicalpreparations are used for the localized effects at the site of theirapplication by virtue of passive drug penetration into the underlyinglayers of skin or mucous membranes. Although some unintended drugabsorption may occur, it is in sub-therapeutic quantities and generallyof minor concern.

Under certain circumstances systemic delivery of drugs via topicalapplication of drug-containing compositions to the skin is desirable.However, permeation across the skin first involves partitioning of thedrug into the stratum corneum, a layer of the epidermis that is highlyimpermeable, particularly to hydrophilic molecules like peptides andproteins. For example, small peptides such as thyrotropin-releasinghormone (362 daltons) and vasopressin (356-358 daltons) are known tohave difficulty in penetrating the skin barrier. Most substances arebelieved to diffuse across the stratum corneum via an intercellularlipoidal route, which is a tortuous pathway of limited frictional volumeand even more limited productive fractional area in the plane ofdiffusion. Once through the stratum corneum, topically applied drugsmust pass through the dermal region through a system of interlockingchannels, through which diffusion is facile and without selectivity.Thus, transdermal systemic delivery of drugs is limited by the poorpermeability of some drugs through the skin and limitations of size ofdrugs that can diffuse through the skin barrier, i.e., less than 500Daltons. Moreover, because only limited amounts of drugs actuallypenetrate the skin layers even when penetration enhancers are applied,this route of administration can only be used for drugs that requirevery small plasma concentration to be effective. For example, thelargest daily dose of drug in transdermal patch form is that ofnicotine, at a dose of only twenty-one milligrams.

Topical administration of drugs to the eye for local delivery has beenused successfully for years, e.g., eye drops for application directly tothe eye or percutaneously absorptive compositions for passive diffusionacross the skin or upper and/or lower eyelid, however, topical drugdelivery for treatment of the posterior segments of the eye posesseveral problems. The posterior segments of the eye are exquisitelyprotected from the external environment, which poses unique and fairlychallenging hurdles for drug delivery. In particular, the conjunctiva isa unique barrier within the eye with tight cell junctions which inhibitthe passage of hydrophilic molecules. Even lipophilic molecules appliedto the eye, for example in the form of eye drops, wash over theconjunctiva quickly, resulting in a true contact time of about ninetyseconds or less, which is not enough time to permit large quantities topass through the conjunctiva. It is somewhat dogmatic that topicalocular delivery is insufficient to achieve therapeutic drug levels inthe posterior segments.

Topical delivery of drugs to the upper eyelid for local delivery to theanterior segments of the eye has been accomplished through inclusion ofan amount of a vasoconstrictor in the topically applied composition orthrough application of the drug near or along the lash line, effectivelyapplying the drug to the surface of the eyeball over time throughblinking action. Inclusion of a vasoconstrictor in certain ophthalmiccompositions, particularly those intended to treat glaucoma, forexample, has significant drawbacks since the vasoconstrictor restrictsblood flow in the immediate area of the eye as well as within the eye,thereby exacerbating the underlying condition.

Thus, there exists a need for methods and compositions for topicaladministration of drugs for local delivery, such as to the eye andparticularly the posterior segments of the eye, as well as for systemicdelivery.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a method for topicaladministration of a drug or combination of drugs for systemic deliverythereof to a human patient comprising applying to at least one eyelid ofa patient a composition comprising the drug or combination. In certainembodiments of this aspect of the invention the composition furthercomprises an effective amount of a muscle fasciculation agent, andoptionally further comprises an effective amount of a permeabilityenhancer. In certain embodiments of this aspect of the invention, themuscle fasciculation agent is caffeine, theophylline, pentoxifyline ortheobromide, which may be included in the topical composition in anamount of up to about 1% and in certain embodiments may be included inan amount of up to about 30 wt % or in certain other embodiments, up toabout 50 wt % of the composition. In some embodiments the compositionmay further comprise in addition to a muscle fasciculating agent, fromabout 0.001 to 50 wt % of an ionotropic agent, such as digitalis.

In another aspect of the invention there is provided a method fortopical delivery of a drug or combination of drugs to the eyeball,eyelid, anterior segments of the eye or posterior segments of the eyecomprising applying to at least one eyelid of a human patient acomposition comprising the drug or combination of drugs. In certainembodiments of this aspect of the invention the composition comprises aneffective amount of a muscle fasciculation agent, and may furthercomprise an effective amount of a permeability enhancer, vasoconstrictoror a vasodilator or both. In certain embodiments, the drug orcombination of drugs is a drug used for ophthalmic treatment, a systemicdrug, a nutrient, hormone or other biological agent and in otherembodiments each drug in the composition is 6000 Daltons or less. Inother embodiments of this aspect of the invention, the musclefasciculation agent is caffeine, theophylline, pentoxifyline ortheobromide, which may be included in the topical composition in anamount of up to about 1% or in certain embodiments up to about 50 wt %.In addition to a muscle fasciculating agent, the compositions mayinclude from 0.001 to 50 wt % of an ionotropic agent, such as digitalis.

In certain embodiments of this aspect of the invention, two differentdrugs are administered by application of a first drug to one eyelid andapplication of a second drug to the other eyelid. In other embodimentsof the invention, uptake of the composition through the eyelid ismanipulated by the applications of the compositions to different areasof the eyelid, e.g., application of a composition containing the activedrug or combination of drugs to the middle portion of the eyelid,followed or preceded by application of a composition comprising avasoconstrictor agent to the border of the eyelid.

In another aspect of the invention there is provided a method oftreating glaucoma comprising topically applying a composition comprisinga therapeutically effective amount of a β-antagonist, α-antagonist,prostaglandin analog, alpha-adrenergic agonist, carbonic anhydraseinhibitor, anti-cholinergic agent, vasodilator, or neuroprotective agenta combination thereof to one or both upper and optionally, lower,eyelids of a patient. In certain embodiments, the composition furthercomprises an amount of a muscle fasciculation agent, such as caffeine,theophylline, pentoxifyline or theobromide effective to facilitatedelivery of the drug to the posterior segment of the eye, and optionallyan effective amount of a permeability enhancer. In some embodiments thecomposition may further comprise in addition to a muscle fasciculatingagent, from about 0.001 to 50 wt % of an ionotropic agent, such asdigitalis.

In another aspect of the invention there is provided a method oftreating dry eye comprising topically applying a composition comprisinga therapeutically effective amount of a parasympathomimetic cholinergicagent (e.g., Pilocarpine, Cevimeline, Carbachol), anticholinesterase(e.g., Echothiophate Iodidide, Isofluorophate, Demecarium Bromide,Physostigmine, Neostigmine, Pyridostigmine, Edrophonium), androgen,estrogen, B-agonist (e.g., isoproternol), alpha-agonist (e.g.,phenylepherine, ephedrine, and the like (alone or in combination) andfrom 0.001% to 50 wt % of a muscle fasciculating agent to one or bothupper and optionally lower eyelids of a human patient. In certainembodiments, the muscle fasciculation agent is caffeine, theophylline,pentoxifyline or theobromide effective and in another embodiment, thecomposition further comprises an effective amount of a permeabilityenhancer. In some embodiments the composition may further comprise inaddition to a muscle fasciculating agent, from about 0.001 to 50 wt % ofan ionotropic agent, such as digitalis.

In other aspects of the invention, the present method and compositioncomprising the appropriate drug(s) or therapeutic agent(s) intherapeutically effective amount(s) and a therapeutically effectiveamount of a micro fasciculating agent is applied for the treatment of aneye disease or condition such as blepharitis, floppy eyelid syndrome,trachomatous dry eye, retinopathy, retinal degeneration, nasolacrimalduct obstruction, epiphora, chalazion, hordeolum, allergicconjunctivitis and keratitis, keratopathy, corneal degeneration,cataract, infectious conjunctivitis and keratitis, pterygium,pinguiculum, iritis, uveitis, keratitis, vitritis, vitreous floaters,vitreous detachment, vitreous hemorrhage, retinal detachment, subretinal hemorrhage, choridal neovascular membrane, retinal edema,macular edema, diabetic retinopathy, retinal hemorrhage, choridalmalignancy, orbital malignancy, eyelid tumors, optic neuritis, opticneuropathy, strabismus, refractive error, glaucoma and the like,lacrimal gland disorders, aging-related ophthalmic conditions.

In yet another aspect of the invention, the present method andcompositions comprising an appropriate drug or therapeutic agent orcombinations of drugs or therapeutic agents is applied to one or moreeyelids to achieve a therapeutically sustainable systemic concentrationof therapeutic agent/drug/combination to treat a condition or diseaseremotely removed from the site of application, e.g., diabetes, systemicinfection, kidney disease, hypertension, heart disease, nicotinewithdrawal, or for administration of hormone replacement therapy.

In another aspect of the invention, a method of treating an ophthalmiccondition is provided in which a composition comprising therapeuticallyeffective amount of one or more active agents for the treatment of theophthalmic condition and a therapeutically effective amount of avasodilator and optionally a therapeutically effective amount of amuscle (or micro) fasciculatinging agent is topically applied to one ormore eyelids of a patient in need thereof. In certain embodiments ofthis aspect of the invention the vasodilator is a phosphodiesteraseinhibitor. In some embodiments the composition may further comprise inaddition to a muscle fasciculating agent, from about 0.001 to 50 wt % ofan ionotropic agent, such as digitalis.

In another aspect of the invention there is provided a method andcomposition for treating cataracts and/or maintaining the health of theidea. The methods and compositions of this aspect of the inventioncomprise topically applying to the outer surface of at least one eyelidof a human patient an ophthalmic composition comprising from about 0.001to 50 wt % caffeine as the sole active agent. In certain embodiments,the composition is applied to at least one eye one time per day. Incertain embodiments, the composition comprises from 10 to 500 mgcaffeine. In other embodiments of this aspect of the invention, thecomposition further comprises from about 0.001 to 50 wt % of anionotropic agent.

In another aspect of the invention there is provided a kit forpercutaneous eyelid administration of one or more therapeutic agentscomprising an applicator and a topical composition or compositionscomprising one or more therapeutic agents. In certain embodiments ofthis aspect of the invention the applicator is a patch containing acomposition of the invention on the surface to be applied to the eyelid;a rollerball applicator integrally connected to a container in which thecomposition is contained; an applicator strip comprising a compositionof the invention on the surface to be applied to the eyelid; a pliablefinger cot containing a composition of the invention as a blisterpositioned on the tip thereof; or an applicator for dipping into asolution of a composition of the invention or an eye stick (structurallysimilar to lipstick, but for application to the outer surface of theupper/lower eyelid).

In another aspect of the invention there is provided a method andcompositions for topical transdermal drug delivery comprisingadministering to the outer surface of the epidermis of an individual acomposition comprising the drug and a muscle fasciculating agent. Incertain embodiments the composition further comprises a permeabilityenhancer. In certain embodiments of this aspect of the invention, themuscle fasciculating agent is caffeine, theophylline, pentoxifyline ortheobromide, which may be included in the topical composition in anamount of up to about 1% and in certain embodiments may be included inan amount of up to about 30 wt % or in certain embodiments, up to about50 wt % of the composition. In some embodiments the composition mayfurther comprise in addition to a muscle fasciculating agent, from about0.001 to 50 wt % of an ionotropic agent, such as digitalis. In certainembodiments of this aspect of the invention the drug is fewer than 6000Daltons in size and in other embodiments the drug is greater than 6000Daltons in size.

In another aspect of the invention there are provided compositions andmethods for enhancing the uptake and providing sustained release of atherapeutic agent comprising topically administering to at least one eyeof a patient a composition comprising the therapeutic agent and a musclefasciculating agent, wherein the composition contacts the underside ofthe eyelid of the at least one eye. In certain embodiments thecomposition further comprises a permeability enhancer. In certainembodiments of this aspect of the invention, the muscle fasciculatingagent is caffeine, theophylline, pentoxifyline or theobromide, which maybe included in the topical composition in an amount of up to about 1%and in certain embodiments may be included in an amount of up to about30 wt % or in certain embodiments, up to about 50 wt % of thecomposition. In some embodiments the composition may further comprise inaddition to a muscle fasciculating agent, from about 0.001 to 50 wt % ofan ionotropic agent, such as digitalis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front view of the left eye, showing (1) the infratrochlearnerve; (2) ophthalmic (orbital) artery; (3) nasocilliary nerve; (4)trochlea; (5) tendon of superior oblique muscle; (6) supratrochlearnerve; (7) superior orbital vein; (8) supraorbital artery, vein andnerve; (9) levator aponeurosis; (10) peripheral and marginal arterialarcades of upper lid; (11) lacrimal artier and nerve terminal branches;(12) orbital lobe of lacrimal gland; (13) palpebral lobe of lacrimalgland; (14) zygomaticotemporal nerve; (15) anterior branch of temporalartery; (16) zygomaticofacial artery and nerve; (17) malar branch oftransverse facial artery; (18) peripheral and marginal arterial arcadesof lower lid; (19) infraorbital artery and nerve; (20) facial artery andvein; (21) angular artery and vein; (22) canaliculi; (23) lacrimal sac;(24) medial canthal tendon-anterior attachment; and (25) dorsal nasalartery.

FIG. 2 is a graph showing the effect of transdermal application to aneyelid of a pilocarpine formulation containing caffeine on human tearproduction.

FIG. 3 is a graph showing the comfort level of subjects aftertransdermal upper eyelid application of a pilocarpine formulation withcaffeine applied to one upper eyelid.

FIG. 4 is a graph showing the effect of transdermal upper eyelidapplication of a timolol plus caffeine formulation on intraocularpressure.

FIG. 5 is a graph showing the percentage change to human systolic bloodpressure and pulse after application to one eyelid of a timolol pluscaffeine.

FIG. 6 is a graph showing the change in Schirmers score after uppereyelid application of a transdermaml physostigmine plus caffeineformulation.

FIG. 7 is a graph showing the effects of upper eyelid application of aformulation containing physostigmine plus caffeine on intraocularpressure in the human eye.

FIG. 8 is a graph showing change in pupil size after transdermal uppereyelid application of a physostigmine plus caffeine formulation.

FIG. 9 is a graph showing the effect of upper eyelid transdermalmonocular application of a physostigmine plus caffeine formulation onheart rate.

FIG. 10 is a graph showing the effect of transdemal application to anupper eyelid of a physostigmine plus caffeine formulation on humansystolic blood pressure.

FIG. 11 is a graph showing the effect of upper eyelid transdermalmonocular latanoprost application on human intraocular pressure.

FIG. 12 is a graph showing the effect of topical application to an uppereyelid of a composition containing brimonidine (without caffeine) onhuman intraocular pressure.

FIG. 13 is a graph showing the effect of topical application to an uppereyelid of a composition containing brimonidine plus caffeine on humanintraocular pressure.

FIG. 14 is a graph showing the effect on a subject's blood glucose levelof a single topical application of insulin/humulin to the upper eyelidof a normal subject.

FIG. 15 is a graph showing the effects on the blood glucose levels ofthree diabetic human subjects of transdermal application to both uppereyelids of a composition containing insulin/humulin.

FIG. 16 is a graph showing the effect of application to one upper eyelidof a composition comprising lisinopril and caffeine on an untreatedhypertensive humansubject's blood pressure.

FIG. 17 is a graph showing the effect on tear production in the treatedand untreated eye after topical application to one upper eyelid of ahuman of a composition comprising pilocarpine (without caffeine)

FIG. 18 is a graph showing the effect on comfort level in the treatedand untreated eye of a human after application to one upper eyelid of acomposition comprising pilocarpine (without caffeine).

DETAILED DESCRIPTION OF THE INVENTION

The present inventive methods, kits and compositions utilize transportvia vascular collaterals or channels within the eyelid to delivertherapeutic agents to specific target tissues that receive blood supply,such as glands, conjunctiva, periocular tissue, the eye including theposterior segments thereof, and even remote target sites via thesystemic circulation. The inventors have discovered that topicalapplication of the therapeutic compositions of the invention to theouter surface of the upper eyelid or eyelids and optionally to at leastone lower eyelid of a human patient greatly aids absorption of anytherapeutic agent. The eyelid is unique in having scant stratum corneum,the epidermis surface layer that retards drug absorption, a very thinepidermis (approximately 40 microns), and no subcutaneous fat. Musclefibers of the Orbicularis muscle that cause the eyelid to blink shut aredirectly beneath the dermis and these muscle fibers can assist drugdelivery by in-pumping drugs through the muscle and it's vascularsystem. The inventors have discovered that these four factors coupledwith a rich circulatory network within the eyelid that can be accessedby the applied drug via the vascular dermis allow percutaneousabsorption of a wider variety of drugs to therapeutic levels compared toapplication of drugs via other routes. Thus, drugs and other therapeuticagents can be applied to the outer skin surface of the eyelid (or theskin of the underside of the eyelid by way of applying an eye dropdirectly to the eye) to specifically target the eyelid glands (accessorylacrimal, lacrimal, meibomian, glands of zeiss and moll); conjunctivalgoblet cells, which secrete the mucinous layer of the tear film; thesub-conjunctival space and conjunctival epithelium; or perioculartissues for drug delivery to these tissues or to the entire eyeballitself. Moreover, the present methods, kits and compositions can beutilized to achieve systemic uptake of therapeutic agent while bypassingthe gastrointestinal (GI) tract and first pass hepatic metabolism.

As used herein the term “drug” means any chemical substance used in thetreatment, cure, prevention, or diagnosis of disease or used tootherwise enhance physical or mental well-being. The term “therapeuticagent” is also used to denote any compound, molecule, or substance usedfor the medical treatment of a disease or condition.

The term “eyelid” as used herein means particularly the upper eyelid(s)of a human subject, but may include the lower eyelid(s) as well. It isunderstood that in each embodiment of the present methods theappropriate therapeutic agent is applied to the outer skin surface of atleast one upper eyelid and optionally to at least one lower eyelidunless expressly stated otherwise.

The term “muscle fasciculating agent” or “micro fasciculating agent” asused herein means any agent that causes a small, local involuntarymuscle contraction (a muscle twitch) such as caffeine, theophylline,pentoxifyline or theobromide.

The term “sustained release” is used herein in its ordinary sense tomean that the compositions of the invention are designed to release adrug slowly over an extended period of time.

In certain aspects, the present methods and compositions take advantageof the unique human upper eyelid anatomy to target drug delivery. Themajor anatomic landmark and demarcation of the upper eyelid is theanteroposterior fascial fusion of the orbital septum and levatoraponeurosis (collagen and elastic fiber extension of the levator musclethat elevates the eyelid) in the superior aspect of the eyelid. Thistissue fuses inferiorly with the connective tissue “backbone” of theupper eyelid called the tarsus. Therefore, the upper eyelid isclassified as having two compartments: one that is “preseptal andpost-septal” in the superior aspect of the upper eyelid and “pretarsaland post-tarsal” in the inferior aspect of the upper eyelid. Theseseparate anatomic and physiologic compartments are not only basicanatomical dogma, but form the critical landmarks used in surgery. Ourunderstanding of physiological functions of the essential function ofthe upper eyelid in maintaining secretory tear function and mechanicalprotection are based upon these well understood anatomical barriers.

Transdermal eyelid drug delivery systems to date have relied almostexclusively on the principle of passive diffusion to transport highlylipid-soluble hormones such as the androgens and estrogens/progestins orsmall molecules, i.e., less than 500 Daltons to permeate in anuntargeted manner throughout the eyelid tissue or have included amountsof vasoconstrictors to facilitate drug absorption in an untargetedmanner. Due to the rigid anatomical barriers that exist within the uppereyelid and to a lesser degree in the lower eyelid, prior methods oftopical drug delivery via the outer surface of the upper (or lower)eyelid have not been satisfactory in regards to targeted drug deliveryto certain segments of the eye (thus have not successfully targeted theentire eyeball) and have not achieved successful systemic delivery oftherapeutic amounts of drug or other therapeutic agents.

In contrast, the methods, kits and compositions of the present inventiondisregard the preconceived dogma regarding anatomical barriers andcompartments of the eyelids, particularly of the upper eyelid. Althoughthese compartments and barriers clearly exist, they are connected by thevascular supply between the two main circulatory systems of the eyelid.These two systems in a broadest sense derive from the internal carotidartery and the external carotid artery system. The vascular branchesfrom these two main arteries provide the eyelid a rich dual bloodsupply. The internal carotid branches supply the inner posterior“post-septal and post-tarsal” compartment and the external carotidbranches serve the outer anterior “preseptal and pretarsal” compartment.

The present inventors discovered that these two circulatory systems,which are extensively linked in the upper eyelid via rich vascularanastomoses can be utilized in the present methods, compositions andkits as a vehicle for transdermal drug delivery from the upper eyelid tospecifically target the accessory lacrimal glands, conjunctival mucosalsecretory apparatus, meibomian glands, the sub-conjunctival space of thepalpebral conjunctiva that reflects into the sub-bulbar conjunctivalspace and to access the periocular and transscleral pathways fortargeting with certain therapeutic drugs. Furthermore, gravity, whichmoves drugs applied to the eyelid inferiorly, is an advantage to thepresent invention in regards to drug delivery to periocular tissue andconjunctiva. Application of the compositions of the present invention tothe upper eyelid results in greater bioavailability of the therapeuticagent(s) with a large surface area in this setting of gravatitionaladvantage. Once the therapeutic agent(s) is secreted into theperi-conjunctival space, the upper eyelid provides a unique mechanicalspreading action to the agent(s). Finally, the present drug deliverymethod reaches any area of the body that is supported by the vasculatorynetwork.

The present invention overcomes several insufficiencies of prior methodsfor subcutaneous or topical delivery of therapeutic agents. For example,the most commonly used non-invasive method for treating the vastmajority of eye diseases and conditions is through the use of eye drops,which are difficult for most people to apply accurately and are washedout or diluted by the tear reflex, reducing the drug's ability to remainin contact with and penetrate the eye. In fact, eye drops are eliminatedfrom the precorneal area in 90 seconds or less, which is so short anexposure period, especially for hydrophilic drugs, that the naturallyoccurring spaces between epithelial cells (e.g., the paracellular routeof drug delivery) are too widespread and coincidental to rely on fordrug delivery therethrough. Thus, eye drops generally result in deliveryof only about 1-5% of the topically administered therapeutic agent.Consequently, most eye drops contain an amount of preservative whichfunctions to punch holes in the corneal epithelium to improveabsorption. Such agents are inherently toxic to the richly enervatedepithelium and cause pain and discomfort to patients. Moreover, eyedrops must be manufactured within a very narrow pH range, which limitsthe types of drugs that can be delivered via this non-invasive route.

Topical delivery of ophthalmic drugs to the eyelid of a patient has beenused previously with limited success. Application of olapatadine,epinastine and muscarinic receptor agonists, small molecules of lessthan 500 Daltons to the surface of the eyelid has been reported toachieve sustained delivery of the drug to the anterior segment of thetreated rabbit eye (US 2009/0209632, US 20090143359 and US 2007/0053964,respectively). It is disclosed in each of these patent applications thatthe amount of release of olapatadine, epinastine or muscarinic receptoragonist to the anterior segment of the eye is controlled by manipulationof the amount of the drug and/or skin permeability through the use ofknown permeability enhancers for application directly to the anteriorsegment of the eye, rather than through systemic blood flow. Systemicabsorption was not observed by these prior methods and hence, deliveryto systemic tissues, the contralateral untreated eye, and the entiretreated eyeball including the posterior segments of the eye was notachieved.

WO 2008/026756 discloses an ophthalmic percutaneous absorptioncomposition for administration to the eyelids which contains avasoconstrictor as an essential component necessary to achieve deliveryof therapeutic agent to the anterior segments of the eye. It isspecifically disclosed that the vasoconstrictor need only have bloodvessel contracting activity in order to effect delivery of the drug intothe anterior segment of the eye. The necessity for inclusion of avasoconstrictor is disadvantageous for treatment of the eye since theseagents decrease blood flow, which in turn causes visual damage fromdiseases where ischemia (poor oxygenation and blood flow) plays a rolesuch as glaucoma, diabetic retinopathy, retinal degeneration, orvascular disease for example.

In contrast, the present inventors have discovered that sustainedrelease and delivery of therapeutic agent to the systemic blood flowand/or all regions of the eye, including the heretofore inaccessibleposterior sections of the eye, can be achieved by topical application ofthe therapeutic agent(s) to the outer surface of one or both uppereyelids and optionally, one or both lower eyelids. The inventors havediscovered that application of a therapeutic compound or drug to one eye(the treated eye) results in drug delivery to the untreatedcontralateral eye as well, via the systemic circulatory system.Moreover, any drug or therapeutic agent having a molecular weight up toand exceeding 6000 Daltons can be administered in this manner andachieve therapeutic concentration at the target site, even when thetarget site is remote from the eyelid, i.e., via the systemiccirculatory system or located within the posterior segments of the eye.

The compositions of the invention comprise a therapeutically effectiveamount of drug appropriate for the condition or disease to be treated.In general, the compositions of the invention comprise therapeutic agentin amounts of from about 0.01 to about 40 wt % of the composition in apharmaceutically acceptable carrier suitable for application to theouter skin surface of the eyelid. The dose and treatment regimen,including administration period of the compositions of the inventionvary depending on the target disease, symptom, patient, administrationroute and the like. The therapeutic agents useful for the presentinvention may be synthetic drugs or may be naturally derived orderivatized. For example, tinctures and natural extracts containingtherapeutic agents may be employed in the compositions and methods ofthe invention. For example, for the treatment of glaucoma, a cream, gel,spray, lotion, ointment, stick applicator, foam, film, or an adhesiveformulation for example containing latanoprost in an amount of about 0.1to 40 wt % of the composition is applied to the upper eyelid. Theinventors have discovered that application of latanoprost to the uppereyelid (and optionally lower eyelid) results in a significant andsemi-permanent decline in intraocular pressure in both the treated anduntreated eye (although a somewhat greater decline in the treated eyewas observed), indicating that the number of applications of latanoprostto achieve the target intraocular pressure can be decreased, e.g., fromonce per day to once every two to four days or longer. The treatmentperiod will vary depending upon the condition being treated and thetherapeutic agent or drug being applied, but in general will range fromabout one day to three months.

In certain embodiments of the invention a muscle contractility agent (amuscle or micro fasciculating agent) is included in the therapeuticcompositions, such as caffeine, theophylline, pentoxifyline,theobromide. The micro fasciculating agent may be included in an amountup to about 50 wt % and this amount will vary depending on the targetsite for drug delivery, e.g. higher amounts of the micro fasciculatingagent may be included when the target is remote (and delivery isachieved systemically) or if the target site is the posterior segment ofthe eye or for sustained delivery. For example, for systemic delivery ofdrug via application to one or both upper eyelids an amount of about 1%by weight or more of a micro fasciculating agent may be included in thecomposition, while for those embodiments where delivery of therapeuticagent to the posterior segment of the eye is desired, an amount of about0.5 to 50 wt %, such as for example 5 wt % of a micro fasciculatingagent may be included in the composition. In certain embodiments,particularly those in which the delivery of therapeutic agent to theanterior portion of the eye is desired, the amount of microfasciculating agent in the composition is in the range of from 0 to 5%,and in other embodiments from 0.001 to 5%. In certain embodiments,particularly when sustained release of the therapeutic agent is desired,the composition may contain up to about 50 wt % of a musclefasciculating agent. In certain embodiments the muscle fasciculatingagent is an appropriate amount of caffeine, which has the benefit ofbeing a naturally occurring and readily metabolized small molecule.

In certain embodiments of the invention, an ionotropic agent may beincluded in the compositions in addition to a muscle fasciculatingagent. Ionotropic agents include any of a class of agents affecting theforce of muscle contraction. Positive inotropic agents increase, andnegative inotropic agents decrease the force of skeletal musclecontraction. The ionotropic agent may be added in an amount of fromabout 0.001 to 50% and the selection of the particular ionotropic agentis made on the basis if the desired effect on muscle contraction.Non-limiting examples of positive inotropic agents that may be includedin the compositions of the invention include Berberine, Bipyridinederivatives, Inaminone, Milrinone, Calcium, Calcium sensitisers,Levosimendan, Cardiac glycosides, Digoxin, Catecholamines, Dopamine,Dobutamine, Dopexamine, Epinephrine (adrenaline), Isoprenaline(isoproterenol), Norepinephrine (noradrenaline), Eicosanoids,Prostaglandins, Phosphodiesterase inhibitors, Enoximone, Milrinone,Theophylline, and Glucagon. In certain embodiments of the invention,digitalis is included in the compositions as an ionotropic agent.

The ophthalmic therapeutic compositions of the invention that do notinclude a micro fasciculation agent may contain one or more of a vastarray of ophthalmic therapeutic agents, alone or in combination, butsuch therapeutic agents do not include olopatadine, muscarinic receptoragonists or epinastine, unless such compositions also include avasodilator and/or vasoconstrictor.

In those aspects of the invention described above, the methods andcompositions take advantage of the extensively linked circulatorysystems in the upper eyelids through application of the therapeuticcomposition to the outer surface of the eyelid(s). However, theinventors have discovered that inclusion of a muscle fasciculating agentin any ophthalmic composition for direct topical delivery to the eyethat upon application to the eye comes into contact with the undersideof the eyelid skin enhances uptake and sustained release of the drug(s)included in the ophthalmic composition. Thus, typical eye dropformulations and gels, for example, that are formulated for directapplication to the eye, are improved by addition of an amount of fromabout 0.01 to up to 50 wt % of a muscle fasciculating agent andoptionally, an ionotropic agent. Such eye drop formulations areencompassed by the present invention.

Vasoconstrictor as an active drug: In certain embodiments of theinvention the sole therapeutic agent(s) of the topical composition isone or more vasoconstrictors. Compositions containing vasoconstrictor asthe sole therapeutic agent(s) are applied to at least one upper eyelidand optionally at least one lower eyelid of the patient for thetreatment of conditions including, but not limited to, redeye, allergicconjunctivitis, blepharitis, puffy eye lids and any disease state orcondition that includes as a symptom edema, vasodilation and/or bleedingin the eyelid, anterior segment, posterior segment or orbit of the eye.In some embodiments, such vasoconstrictor-containing compositions mayalso contain from 0 to 1% or more as required of a micro fasciculatingagent, such as for example, caffeine, theophylline, pentoxifyline ortheobromide and/or a permeation enhancer agent. Further,vasoconstrictors may be combined with other active agents, and/or microfasciculating agent, permeation agent, and the like. Although anyvasoconstrictor may be used in the compositions and methods of thepresent invention, certain embodiments employ a therapeuticallyeffective amount of ephedrine. Other embodiments of this aspect of theinvention include use of a vasoconstrictor such as for examplemethoxamine, phenylyephrine, oxymetazoline, cocaine, Allerest®,naphazoline, Visine®, tetrahydrolozine, Op-Thal-Zin/zinc sulfate,Rhindecon, phenylpropanolamine, Sudafed®, pseudoephedrine, Ephed II,ephedrine, Aramine, metaraminol, Epifrin, epinephrine, Levophed,norepinephrinand nicotine.

In those embodiments of the invention in which a vasoconstrictor isincluded in the topical treatment regimen, the vasoconstrictor may beapplied to the eyelid separate from a second topical compositioncomprising other active agents, microfascilitating agent, optionalpermeating agent and optional ionotropic agent. The vasoconstrictorcontaining composition may be applied to the same area of the eyelid asthe second topical composition or may instead be applied to theperimeter of the area of the eyelid onto which the second topicalcomposition was applied. Application to the perimeter region is believedto limit the effects of the vasoconstrictor and thereby limit anyunwanted side effects, while limiting systemic flow of the active agent.Application of a vasoconstrictor and active agent in this manner may beachieved through use of separate applicators or through application of acomposition formulated as a stick applicator (an “eyelidstick”) in whichthe active ingredients (other than vasoconstrictor), any permeatingagents, muscle fasciculating agent and/or ionotropic agnet comprise themiddle of the eyelidstick and the perimeter of the eyelidstick comprisesthe vasoconstrictor, resulting in application of a small amount ofvasoconstrictor on the perimeter of the application area. In anotherembodiment, the vasoconstrictor is impregnated on the border of aneyestrip or film applicator with active agent(s), and/or microfasciculating agent, ionotropic agent and/or permeating agentimpregnated in the middle of or throughout the entire applicator.Application of the strip to the eyelid and subsequent removal results inlocalized application of the various components (e.g., a border ofvasoconstrictor).

Vasodilator as the active drug: Classes of vasodilator agents that maybe included in the compositions as the sole therapeutic agent(s) or incombination with a vasoconstrictor or other therapeutically active agentinclude alpha-blockers (alpha-adrenoreceptor antagonists), ACEinhibitors (angiotensin converting enzymes), angiotensin receptorblockers, β2 agonists (β2-adrenoceptor agonists, calcium channelblockers, centrally acting sympatholytics, direct acting vasodilators,endothelin receptor antagonists, ganglionic blockers, nitrodilators,phosphohodiesterase inhibitors, potassium channel openers, and rennininhibitors. Specific examples of vasodilators that may be used in themethods and compositions of the invention include, but are not limitedto: arginine, bencyclane fumarate, benzyl nicotinate, bupheninehydrochloride, ciclonicate, cyclandelate, ethyl nicotinate, hepronicate,hexyl nicotinate, hydralazine, inositol nicotinate, isoxsuprinehydrochloride, methyl nicotinate, minoxidol, naftidrofuryl oxalate,nicametate citrate, niceritrol, nicoboxil, nicofuranose, nicotinylalcohol, nicotinyl alcohol tartrate, nitric oxide, nitroglycerin,nonivamide, oxpentifylline, papaverine, papaveroline, pentifylline,peroxynitrite, pinacidil, sodium nitroprusside, suloctidil, teasuprine,thymoxamine hydrochloride, tolazoline, vitamin E nicotinate, andxanthinol nicotinate. Centrally acting vasomodulatory agents includeclonidine, quanaberz, and methyl dopa. Alpha-adrenoceptor blockingagents include indoramin, phenoxybenzamine, phentolamine, and prazosin.Adrenergic neuron blocking agents include bedmidine, debrisoquine, andguanethidine. ACE inhibitors include benazepril, captopril, cilazapril,enalapril, fosinopril, lisinopril, perindopril, quinapril, and ramipril.Ganglion-blocking agents include pentolinium and trimetaphan. Calciumchannel blockers include amlodipine, diltiazem, felodipine, isradipine,nicardipine, nifedipine, nimodipine, and verapamil. Prostaglandinsincluding: prostacyclin, thrombuxane A2, leukotrienes, PGA, PGA1, PGA2,PGE1, PGE2, PGD, PGG, and PGH. Angiotensin II analogs include saralasin.Such compounds may be applied to the eyelid as the sole active componentof a topical composition with or without any of a micro fasciculatingagent, permeating agent or ionotropic agent for therapeutic treatment ofthe posterior segment of the eye, to treat the optic nerve or retina,for example or to treat conditions such as glaucoma, ischemicretinopathy (diabetic, hypertensive, degenerative) and the like.

Compositions containing a therapeutically affective amount of avasodilator, as the sole active agent or in combination with othertherapeutically active agents, and optional micro fasciculating agent,ionotropic agent and/or permeating agent may be used in the treatment ofa variety of ophthalmic conditions by application to at least one eyelidof a patient in need thereof. The vasodilator species and concentrationwithin the transdermal drug delivery formulation may be different foreach drug and for each delivery requirement. There may be one or morevasodilator, acting in a similar or different mechanism within the sameformulation. There may also be vasodilators that are added in tandemtemporally or simultaneously to induce the optimal reaction and tocreate a tissue concentration profile of the vasodilators that optimizesthe transdermal transportation of the drug into the tissue or thebloodstream. The vasodilator may serve exclusively as the vasodilationagent or it may also, in addition, serve other functions to the deliverycomplex such as to assist in the penetration of the active drug moleculeor the penetration of the other components of the delivery vehicle. Thevasodilator may also co-function by definition and by action as theactive drug agent, or to a serve another undefined function to createthe optimal chemistry of the delivery vehicle formulation.

In another embodiment of this aspect of the invention, a vasodilator andvasoconstrictor may be used in combination in the compositions andmethods of the invention. For example, an active drug, vasodilator, andvasoconstrictor in a formulation, optionally with a penetrating,ionotropic agent and/or micro fasciculating agents can be applied to theeyelid. The time release aspect of the vasodilator and vasoconstrictoraffects both drug delivery destination and activation. In anotherembodiment, a fast acting vasodilator is employed in the compositionsand methods to immediately increase blood flow and, therefore, increasedrug absorption immediately upon drug application. This may be followedby topical application to the same eyelid(s) of a delayed actingvasoconstrictor which acts to sequester the drug at the treatedsite/eyeball thereby preventing systemic absorption and increasing localactivity of drug. In yet another embodiment, a short actingvasoconstrictor is applied to at least one upper eyelid to preventsystemic blood flow followed by application to the eyelid of a delayedacting vasodilator, which then causes increased delivery systemically.Additionally, since vasoconstrictor use decreases blood flow locally tothe eye and often results in worsening of ischemic eye diseases such asglaucoma or diabetic retinopathy, the use of a vasodilator incombination therewith serves to diminish this negative effect whileenabling the use of the least amount of vasoconstrictor necessary.

Caffeine as the active drug. Caffeine has been shown to have certainanti-oxidant properties and to provide protection against cataractformation and reduce cataracts in test animals when applied directly tothe eye in the form of eye drops. Application of caffeine to the outersurface of at least one eyelid of a human patient via the methods andcompositions of the invention eliminates the unpleasant effects of eyedrops and results in delivery of higher concentrations of caffeine tothe target site within the eye than is attainable with eye drops, whichare primarily washed away by blinking. Moreover, because caffeine causesmicro fasciculation in the eyelid muscle, sustained release of caffeineis attained by application of the composition directly to one or botheyelids. Consequently, the caffeine composition need only be appliedonce per day in many instances, although multiple applications per dayare also contemplated depending on the physical condition of the treatedeye(s).

The caffeine containing compositions of this aspect of the invention canbe formulated to contain from 0.001 wt % to 50 wt % caffeine. In certainembodiments, the compositions are formulated to contain from about 0.001to 500 mg caffeine, although the compositions may be formulated todeliver any desired amount of caffeine. The compositions may alsoinclude an inotropic agent to enhance muscle twitching, such as from0.001 to 50 wt % of the composition. Permeation enhancers may also beincluded in the compositions.

Application of caffeine to at least one eyelid serves to reduce theoxidative stress within the treated and untreated eye, thus helping tomaintain the health of the eye and prevent oxidative damage. Inparticular, application of caffeine to at least one eyelid aids ininhibiting the formation of cataracts. Moreover, application of caffeineto at least one eyelid of a individual suffering from cataract(s)reduces the growth of and/or slows the further growth of thecataract(s). Typically the caffeine-containing composition is applied tothe eyelid of the affected eye(s), but because caffeine reaches both thetreated and untreated eye, it is not necessary to apply directly to theeyelid of the affected eye.

Ophthalmic Compositions in General: Ophthalmic compositions of theinvention can be formulated to contain therapeutic agent or drug(s) forthe treatment of watery eyes or epiphora, that can, for example, be dueto overactive tearing reflex (from dry eye, for example), keratitis,photophobia, allergic conjunctivitis or nasolacrimal duct obstructionincluding pharmaceutically effective amounts of atropine, scopolamine,homoatropine, cyclopentalate, tropicamide and the like andanticholinergic agents such as combinations thereof. Allergic eyedisease generally involves an allergic reaction of the ocular mucosa andthe conjuntiva. Seasonal keratoconjucntivitis, perennial allergicconjunctivitis, vernal keratoconjuntivitis and atopic conjunctivitis aresuccessfully treated with the compositions, kits and methods of theinvention. Meibomian glandular dysfunction, blepharitis, rosacea,chalazion, and hordeolum may be treated according to the methods of theinvention by topical application to at least one eyelid of a compositionof the invention containing one or more cholinergic agents,antiinflammatory drug, or antibiotic. The therapeutic agents that may beincluded include pilocarpine, cyclosporine A, carbachol, echothiophateiodide, diisopropyl fluorophosphates, physostigmine, neostigmine,dipivefrin, apraclonodine, isoproternol, bromocriptine orphenylepherine, and antibiotics such as the tetracycline class,aminoglycosides, cephalosporins, antifungals (e.g., Neomycin andPolymixin) and the like appropriate for the condition to be treated, andoptionally, up to about 50% of a micro fasciculating agent, such ascaffeine, theophyline or theobromine, for example. Generally, the drugtargets the meibomian glands to improve the lipid layer of the tearfilm, which improves tear stability, decreases evaporation and improvestear spread.

Traditionally, treatment of dry eye, dry mouth (Sjögren's Syndrome) orblepharitis, for example, has included oral administration (systemicdelivery) of the appropriate therapeutic agent, such as the secretogues,pilocarpine, pilocarpine extract or tincture and physostigmine, whichare indicated for dry eye and dry mouth and antibiotics such asoxytetracycline have been orally administered for the treatment ofblepharitis. Unfortunately, systemic cholinergic stimulation isaccompanied by numerous unwanted side effects including sweating,bracycardia, hypotension, nausea, vomiting and increased urination,while antibiotics are simply not tolerated by many people.

The compositions and methods of the present invention enable topicaladministration of drugs such as secretogues, e.g., pilocarpine (which isa muscarinic receptor agonist as well as a cholinergic agent) andphysostigmine, alone or in combination with a micro fasciculating agent,directly to the eyelid (one or both eyelids) with or without the use ofvasoconstrictors, for delivery to the target site, e.g., the lacrimalglands, meibomian glands, conjuctival goblet cells, resulting insecretions from all three layers of tear film. Similarly,anti-inflammatories, such as cyclosporine (molecular weight 1202Daltons), which is typically applied to dry eye via eye drops that causea stinging sensation in up to 20 to 30% of patients and require monthsto achieve varying degrees of efficacy, may be applied via the presentmethods, thus avoiding unpleasant side effects and resulting in deliveryof the drug through the eyelid to the accessory lacrimal, lacrimal, andconjuntival mucosa and meibomian glands, thus achieving therapeuticeffect in less time than previously observed.

The methods and compositions of the present invention may be applied tothe treatment of various ophthalmic conditions and diseases includingblepharitis, floppy eyelid syndrome, trachomatous dry eye, retinopathy,retinal degeneration, nasolacrimal duct obstruction, epiphora,chalazion, hordeolum, allergic conjunctivitis and keratitis, infectiousconjunctivitis and keratitis, pterygium, pinguiculum, iritis, uveitis,keratitis, vitritis, vitreous floaters, vitreous detachment, vitreoushemorrhage, retinal detachment, sub retinal hemorrhage, choridalneovascular membrane, retinal edema, macular edema, diabeticretinopathy, choridal malignancy, orbital malignancy, eyelid tumors,optic neuritis, optic neuropathy, strabismus, refractive error, andglaucoma. The ophthalmic compositions of the invention used to treatthese various conditions and diseases comprise the appropriate activeingredient for treatment, such as anti-inflammatory agents (steroidalanti-inflammatory agents such as prednisone, triamcinolone,dexamethasone, Durezol, Fluoromethalone, loteprendol, and the like;non-steroidal anti-inflammatory drugs (NSAIDs) such as ketorolac,bromphenac, nephenac, and the like, and immunosuppressive agents, suchas: cyclosporine, tacrilimus, sirolimus, and the like); Dry Eye SyndromeAgents such as cholinergics which include (a) muscarinic receptoragonists (Pilocarpine, Cevimeline, Carbachol), (b) anticholinesteraseagents: physostigmine, neostigmine, echothiophate iodide,pyridostigmine, edrophonium; Beta-agonists such as Isoproternol;Alpha-agonists (e.g., brimonidine, iopidine, epinepherine,phenylepherine, all vasoconstrictors; tetracycline class antibiotics(e.g., for Rosecea) such as doxycycline, tetracycline; estrogens andandrogens; and immunosupressives such as cyclosporine, and the like;Antiglaucoma agents such as Betaantagonists, Alpha-antagonists, carbonicanhydrase inhibitors, prostaglandin analogs (e.g., in certainembodiments, a skin bleaching agent or anti melanocytic agent may beadded to the compositions to prevent skin darkening (e.g.,hydroquinone), anticholinergic compounds (including muscarinic receptoragonists), vasodilators. Possible glaucoma drug combinations includeB-antagonist and alpha-antagonist, B-antagonist and carbonic anhydraseinhibitor, B-antagonist and prostaglandin analog, anticholinergic(including muscarinic agonists) and alpha-agonist, any Intraocularpressure lowering agent and vasodilator, any intraocular pressurelowering agent and neuroprotective agent; antibiotics such asCephalosporins, Fluoroquinolone(ciprofloxacin, moxifloxacin,gatifloxacin), Macrolide(erythromycin, azithromycin, etc), Tetracyclineclass, Aminoglycosides(Tobramycin, gentamycin), Trimethoprim,Sulfonamides, and the like; Antihistamines such as emedastine,levocabastine, antazoline, pheniramine, azelastine, and the like; mastcell stabilizers such as lodoxamide, olopatadine, Ketotifen, CromolynSodium and the like; ocular decongestants such as Naphazoline,Phenylepherine, Tetrahydrozoline, Oxymetazoline, and the like; Anti-VEGF(vascular endothelial growth factorsuch as Lucentis ranibizumab andAvastin (bevacizumab); Anti EGFI (epidermal growth factor inhibitor)Erlotinib(Tarceva), Gefitinib(Iressa); Neuroprotective agents such asMemantine(Namenda), Cholesterol lowering Medications including statins,IOP lowering agents that are also neuroprotective(Brimonidine(Alphagan),Betaxolol(Betoptic); herbal agents, including various extracts, ginkobiloba, and the like; vitamins, minerals, and the like; andoligonucleotides.

In another aspect of the invention, compositions comprising atherapeutically effective amount of a desired therapeutic agent orcombination of therapeutic agents and from about 0.001 to 50 wt % musclefasciculating agent are formulated for topical transdermaladministration. In this aspect of the invention, the composition isadministered to any outer skin surface of a patient. Any drug ortherapeutic agent that can be applied transdermally can be used incombination with a muscle fasciculating agent and optional ionotropicagent as described herein and formulated in any convenient form fortopical administrations, such as a lotion, crème, patch, and the like.In certain embodiments the composition further comprises a permeabilityenhancer. In certain embodiments of this aspect of the invention, themuscle fasciculating agent is caffeine, theophylline, pentoxifyline ortheobromide, which may be included in the topical composition in anamount of up to about 1% and in certain embodiments may be included inan amount of up to about 30 wt % or in certain other embodiments, up toabout 50 wt % of the composition. In certain embodiments of this aspectof the invention the drug(s) is less than 6000 Daltons in size, while inother embodiments the drug may be larger than 6000 Daltons in size.Non-limiting examples of drugs that may be included in the compositionsfor topical transdermal delivery include insulin, recombinant insulin,botox, myobloc, antihypertensive agents, nicotine, antibiotics,hormones, recombinant hormones, and anti-arrhythmic agents. The musclefasciculating agent serves to stimulate subcutaneous muscle, whichserves to increase absorption of the active agent into muscle. Anoptional ionotropic agent serves to enhance the muscle contractions,further enhancing absorption of the drug. Since muscle is highlyvascular, increasing absorption into muscle results in increasedabsorption of the drug into the body.

Optionally, an amount of a penetrating agent may also be included in anyof the compositions of the invention to aid penetration of the activecomponent into and across the skin or eyelid skin such as for example,aliphatic alcohol, fatty acid and a salt thereof, fatty acid ester,polyalcohol alkyl ether, polyoxyethylene alkyl ether, glyceride,polyalcohol medium chain fatty acid ester, polyoxyethylene sorbitanfatty acid ester, alkyl lactate ester, terpenes and organic amine. Morespecifically, the percutaeous penetrating agent may be ethanol,glycerol, diethylene glycol, propylene glycol, polyethylene glycol andhigher aliphatic alcohols (saturated or unsaturated higher aliphaticalcohol having 12 to 22 carbon atoms such as oleyl alcohol, laurylalcohol and stearyl alcohol), capric acid, myristic acid, palmitic acid,lauric acid, stearic acid, isostearic acid, oleic acid, linoleic acidand linolenic acid, and a salt thereof (for example, sodium salt,potassium salt, magnesium salt, calcium salt and aluminium salt),include an ester of a fatty acid such as myristic acid, palmitic acid,lauric acid, stearic acid, isostearic acid, oleic acid, linoleic acid,linolenic acid, propionic acid, butyric acid, isobutyric acid, valericacid, pivalic acid, caproic acid, heptanoic acid, malonic acid, succinicacid, glutaric acid, adipic acid, pimelic acid, crotonic acid, sorbicacid, maleic acid, fumaric acid and sebacic acid with a lower aliphaticalcohol such as methanol, ethanol, propanol, isopropanol, butanol,pentanol, hexanol, heptanol and octanol, isopropyl myristate, isopropylpalmitate, diisopropyl adipate and diethyl sebacate, an ether of apolyalcohol such as glycerol, ethylene glycol, propylene glycol,1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol,polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan,sorbitol, methyl glucoside, oligosaccharide and reduced oligosaccharidewith alkyl alcohol, polyoxyethylene lauryl ether, polyoxyethylene cetylether, polyoxyethylene stearyl ether and polyoxyethylene oleyl ether,glycerol ester of fatty acid having 6 to 18 carbon atoms (e.g;,monoglyceride, diglyceride, triglyceride and a mixture thereof),glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate,glyceryl monooleate, glyceryl dilaurate, glyceryl dimyristate, glyceryldistearate, glyceryl trilaurate, glyceryl trimyristate and glyceryltristearate, ethylene glycol monocaprylate, propylene glycolmonocaprylate, glycerin monocaprylate, mono 2-ethylene glycolethylhexanoate, mono 2-propylene glycol ethylhexanoate,di(2-propylene)glycol ethylhexanoate, propylene glycol, dicaprylate,polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitanmonostearate and polyoxyethylene sorbitan monooleate, methyl lactate,ethyl lactate, methyl 2-methoxy propionate and ethyl2-methoxypropionate, monoethanolamine, triethanolamine, creatinine andmeglumine. In certain embodiments of the invention one or more of fattyacid ester, polyoxyethylene, isopropyl myristate and polyoxyethyleneoleyl ether is included in the composition. In other embodiments of theinvention a penetrating agent or combination of agents such as1-acyl-azacycloheptan-2-one (azone), 1-acyl-glucoside,1-acyl-poly(oxyethylene), 1-acyl-saccharide, 2-(n-acyl)-cyclohexanone,1-alkanol, 1-alkanoic acid, 2-(n-acyl)-1,3-doxolane (SEPA),1,2,3-triacylglyceride, 1-alkylacetate, alkyl-sulfate, dialkyl sulfate,and phenyl-alkyl-amine may be added to the composition.

Also optionally, an amount of a hydrating agent such as hyaluronic acid,saline solution, polyvinylpyrrolidone, may be included in any of thecompositions of the invention. Ophthalmic compositions of the inventionthat are intended to penetrate the stratum corneum generally, althoughnot necessarily, include an amount of a hydrating agent to facilitatepenetration of the therapeutic agent through the cell junctions of thestratum corneum.

When included in the compositions of the invention, penetrating agentsare generally in the amount of from 0.01% to 50% by weight of thecomposition and in some embodiments from 0.1% to about 40% by weight ofthe composition, 1% to about 35% and in other embodiments from about 5%to about 30% by weight of the composition and the amount of hydratingagent is in the range of from 0.001% to 30% by weight of thecomposition, in other embodiments from 0.01 to 25% by weight of thecomposition and in still other embodiments, from 0.1% to 10% by weightof the composition.

The compositions of the invention may be formulated as a cream, gel,lotion, ointment, stick, spray, foam, film, strip, tape, poultice,plaster, adhesive preparation or the like for direct application to theskin or to the outer surface of the upper eyelid or may be adhered to apatch, strip, tape, poultice, plaster and the like that is suitable forapplication to the skin or to the outer surface of the upper eyelid.Because drug delivery through the eyelid is so effective, thecompositions for application to the eyelid can be formulated to containless drug or therapeutic agent than is routinely administered via eyedrops or for systemic delivery (e.g., via injection, oral dosage, andthe like) to treat the condition via topical application. Moreover,because the composition for application to the outer surface of theeyelid is not applied directly to the eye, the pH of these formulationsof the invention can range from 0 to 14, enabling the use of a widerange of therapeutic agents that ordinarily cannot be formulated fortopical application to the eye. Also, because there is little or nolimitation on the pH of the compositions of the invention, pH can bemanipulated to maximize penetration of drug through the eyelid. Bymanipulating pH of the composition, it is possible to maximizepenetration of unbound therapeutic agent through the skin.

In addition to the components discussed above, any component generallyused for manufacturing medicine in the desired form can be added to thepresent compositions of the invention, if desired. Examples of suchcomponents include a base matrix for adhesive preparations, an ointmentbase, gel base, solvent, oil, crosslinking agent, surfactant, gum,resin, pH adjuster, stabilizer, antioxidant, preservative, ultravioletabsorbent and wetting agent. A percutaneous absorption enhancer can beadded, if desired.

The base matrix for an adhesive preparation may include an acrylicpressure sensitive adhesive, a silicone pressure sensitive adhesiveand/or rubber pressure sensitive adhesive, for example. The matrix canbe retained on one surface of a support generally used in a preparationto be applied to the skin surface such as tape, patch, cataplasma andplaster, or on one surface of a support composed of any material havingno adverse effect on the present invention.

An acrylic pressure sensitive adhesive may include acrylic acid-octylacrylate copolymer, acrylate-vinyl acetate copolymer, 2-ethylhexylacrylate-vinyl pyrrolidone copolymer and/or methacrylic acid-butylacrylate copolymer. Silicone pressure sensitive adhesives useful incertain embodiments of the invention include polymethylphenylsiloxanecopolymer and/or acrylic acid-dimethylsiloxane copolymer, for example.Rubber pressure sensitive adhesives that may be used in certainembodiments of the invention include for examplestyrene-isoprene-styrene copolymer, natural rubber, polyisobutylene,polybutene and/or ethylene-vinyl acetate copolymer (EVA), to whichtackifier resin, softener and the like can be added, if desired.

Ointment based formulations may include fat and oil bases such asVaseline®, paraffin, plastibase, silicone, vegetable oil, lard, wax andunguentum simplex; and/or emulsion bases such as hydrophilic ointment(vanishing cream), hydrophilic Vaseline®, absorption ointment, hydrouslanolin, purified lanolin and hydrophilic plastibase (cold cream).

Gel based formulations may include thickening polymers such ascarboxyvinyl polymer, polyacrylic acid, sodium polyacrylate,methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethyleneoxide, polyacrylamide, gelatine, acacia gum, tragacanth, guar gum,xanthan gum, agar, chitosan and carageenan; fatty acid esters such asisopropyl myristate, isopropyl palmitate and propylene glycol oleate;fatty acids such as lactic acid, lauric acid, oleic acid, linoleic acidand linolenic acid; aliphatic alcohols such as lauryl alcohol and oleylalcohol; and hydrocarbons such as squalene and squalane.

Solvents used in the manufacture of the compositions of the inventionmay include purified water, methanol, ethanol, 1-propanol, loweralcohol, ethyl acetate, diethyl ether, tert-butylmethyl ether,pyrrolidone, acetic acid, acetonitrile, N,N-dimethylformamide, acetone,methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran,chloroform, toluene and xylene, and the like.

Oils used in the manufacture of the compositions of the invention mayinclude volatile or involatile oil, solvent and resin. Oil is generallyused in an external preparation for skin and may be in a liquid, pasteor solid form at room temperature. Specifically, for example, higheralcohols such as cetyl alcohol and isostearyl alcohol; fatty acids suchas isostearic acid and oleic acid; polyalcohols such as glycerol,sorbitol, ethylene glycol, propylene glycol and polyethylene glycol; andesters such as myristyl myristate, hexyl laurate, decyl oleate,isopropyl myristate and glyceryl monostearate can be mentioned.

When included, a crosslinking agent may be for example a polyisocyanate,organic peroxide, organometallic salt, alkoxide and metal chelate,examples of which are well known in the art of manufacturing topicalmedications for use in humans.

Surfactant may be included in the compositions of the invention tofacilitate dissolution of formulation components and/or absorption,including anionic surfactant, cationic surfactant, nonionic surfactantand amphoteric surfactant. Useful surfactants include fatty acid salt,alkyl sulfate, polyoxyethylene alkyl sulfate, alkyl sulfo carboxylate,alkyl ether carboxylate, amine salt, quanternary ammonium salt,polysorbate 80, polyoxyethylene hydrogenated castor oil, polyoxyethylenefatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitanfatty acid ester, alkyl betaine, dimethylalkylglycine and lecithin.

If desired, gum and/or resin may be included in the compositions of theinvention, including for example, sodium polyacrylate, cellulose ether,calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer,vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer,nitrogen-substituted acrylamide polymer, polyacrylamide, cationicpolymer such as cationic guar gum, dimethylacrylic ammonium polymer,acrylic acid-methacrylic acid copolymer, polyoxyethylene-polypropylenecopolymer, polyvinyl alcohol, pullulan, agar, gelatine, chitosan,polysaccharide from tamarindo seed, xanthan gum, carageenan,high-methoxyl pectin, low-methoxyl pectin, guar gum, acacia gum,microcrystalline cellulose, arabinogalactan, karaya gum, tragacanth gum,alginate, albumin, casein, curdlan, gellan gum, dextran, cellulose,polyethyleneimine, high polymerized polyethylene glycol, cationicsilicone polymer, synthetic latex, acrylic silicone,trimethylsiloxysilicate and fluorinated silicone resin.

A pH adjuster may be used in the compositions to adjust pH of thecomposition to a desired range, such as pH 4-10, or pH 5-8, for exampleor any range that maximizes the penetration through the skin of theparticular drug in the composition. pH adjustment can be achievedthrough use of various chemicals such as hydrochloric acid, citric acid,sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinicacid, tartaric acid, L-sodium tartrate, sodium hydrate, potassiumhydrate, sodium carbonate, sodium hydrogencarbonate, lactic acid,calcium lactate, sodium lactate, sodium fumarate, sodium propionate,boric acid, ammonium borate, maleic acid, phosphoric acid, sodiumhydrogenphosphate, dl-malic acid, adipic acid, triethanolamine,diisopropanolamine, meglumine, monoethanolamine, sulfuric acid andaluminum potassium sulfate and the like.

Stabilizers may optionally be included in the compositions of theinvention. Useful stabilizers include for example sodium bisulfite,sodium sulfite, sodium pyrosulfite, sodium formaldehyde sulfoxylate,L-ascorbic acid, erythorbic acid, L-cysteine, thioglycerol, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,ascorbyl palmitate, dl-.alpha.-tocopherol, nordihydroguaiaretic acid,1-hydroxyethylidene-1,1-diphosphonic acid, disodium edetate, tetrasodiumedetate dehydrate, sodium citrate, sodium polyphosphate, sodiummetaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbicacid and/or succinic acid.

Other optional components of the compositions include wetting agentssuch as glycerol, polyethylene glycol, sorbitol, maltitol,propylene-glycol, 1,3-butanediol and hydrogenated maltose syrup;antioxidants such as sodium bisulfite, sodium sulfite, sodiumpyrosulfite, sodium formaldehyde sulfoxylate, L-ascorbic acid,erythorbic acid, L-cysteine, thioglycerol, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbyl,palmitate, dl-.alpha.-tocopherol and nordihydroguaiaretic acid;preservatives such as methylparaben, propylparaben, chlorobutanol,benzyl alcohol, phenylethyl alcohol, benzalkonium chloride, phenol,cresol, thimerosal, dehydroacetic acid and sorbic acid; ultravioletabsorbent such as octyl methoxycinnamate, glyceryl monooctanoatedi-para-methoxy cinnamate, 2-hydroxy-4-methoxybenzophenone,para-aminobenzoic acid, para-aminobenzoic acid glycerol ester,N,N-dipropoxy-para-aminobenzoic acid ethyl ester,N,N-diethoxy-para-aminobenzoic acid ethyl ester,N,N-dimethyl-para-aminobenzoic aid ethyl ester,N,N-dimethyl-para-aminobenzoic acid butyl ester, homomethylN-acetylanthranilate, amyl salicylate, menthyl salicylate, homomethylsalicylate, octyl salicylate, phenyl salicylate, benzyl salicylate andp-isopropyl phenyl salicylate.

The formulations of the invention may be in any form, e.g., gels,creams, lotions, and the like. The formulations are not limited in formand may include for example liposomes and other vesicles, such astransfersomes, which include surface active agents and are particularlyuseful for the transdermal delivery of large molecules such as peptideand proteins; and thosomes, which are liposomes that contain ethanol,which functions as a permeation enhancer.

The following tables provide non-limiting examples of excipients (andamounts thereof) that may be included in the inventive compositions.

Gel Formulations:

Class Excipients Polymers Methyl cellulose HydroxyethylcelluloseHydropropylcellulose Hydroxypropylmethyl cellulose Sodium carboxy methylcellulose Carbopol Chitosan Poloxamer (Pluronics ®) Sodium alginatePolyvinyl alcohol Xanthan gumCream Formulations:

Class Excipient Hydrophobic Stearic acid excipients Palmitic acid Lauricacid Capric acid Mineral oil Bees wax Silicone oil Emulsifiers Stearylalcohol (Hydrophobic and Cetyl alcohol Hydrophilic) Glycerylmonostearate Polyethylene glycol monostearate Sorbitan monostearateSorbitan monolaurate Sorbitan monopalmitate Sorbitan monostearateSorbitan monoleate Sorbitan sesquiolate Sorbitan trioleate Cetarylalcohol Cetereth 20 (ethoxylated derivative of cetaryl alcohol) Sodiumstearoyl-2-lactylate Calcium stearoyl-2 lactylate Polysorbate Sodiumlauryl sulfate Stearyl colamino formyl methyl pyridinium chloride Sodiumborate Polyoxyethylene lauryl alcohol Polyoxylated oleyl alcoholPolyoxyethylene stearate Polyoxyethylene sorbitan monostearatePolyoxyethylene glycol monostearate Propylene glycol monostearateEthoxylated lanolin Ethoxylated cholesterol Hydrophilic Purified waterexcipients Buffers Polymers (as outlined for gels) Humectants GlycerinSorbitol Propylene glycol Polyethylene glycol (low molecular weight)

Ointment Formulations:

-   Petrolatum-   White wax-   Lanolin-   Mineral oil-   Bees wax-   Microcrystalline-   wax-   Cholesterol-   Cetyl alcohol-   Stearyl alcohol-   Sorbitan-   sesquioleate-   Lanolin alcohol

Exemplary Preservatives that May be Included in the Compositions of theInvention:

Preservatives Bithional Butyl p- hydroxybenzoate p-chloro-m-xylenolDehydroacetic acid Ethyl paraben Methyl-p- hydroxybenzoate Propyl-p-hydroxybenzoate Sorbic acid

Exemplary Hydrating Agents that May be Included in the Compositions ofthe Invention and Exemplified Amounts Thereof:

Excipient FDA Maximum Potency LACTIC ACID TOPICAL; EMULSION, CREAM:1.00% TOPICAL GEL: 6.07% TOPICAL LOTION: 5.70% TOPICAL OINTMENT: NOTKNOWN TOPICAL SUSPENSION: 0.70% TOPICAL SOLUTION: 18.06% SORBITOLTOPICAL; EMULSION: 7.00% TOPICAL; EMULSION, CREAM: 67.52% TOPICAL;LOTION: NOT KNOWN GLYCERIN TOPICAL; CREAM: 4.0% TOPICAL; CREAM,EMULSION,: 2.0% TOPICAL; EMULSION, CREAM: 20.0% TOPICAL; GEL: 20.0%TOPICAL; LOTION: 50.0% TOPICAL; OINTMENT: NOT KNOWN TOPICAL; SOLUTION:50.0% TRANSDERMAL; GEL: 5.0% HEXANETRIOL TOPICAL; EMULSION, CREAM: 7.50%(1,2,6- HEXANETRIOL) PROPYLENE TRANSDERMAL GEL: 6.0% GLYCOL TOPICALOINTMENT: 38% TOPICAL LOTION: 59% TOPICAL GEL: 98.09% TOPICAL EMULSIONCREAM: 71.08% HEXYLENE TOPICAL; EMULSION, CREAM: 12.0% GLYCOL TOPICAL;GEL: 2.0% TOPICAL; OINTMENT: 12.0% TOPICAL; SOLUTION: 12.0% TOPICAL;SOLUTION: 29.70% POLYETHYLENE TOPICAL; OINTMENT: 39.0% GLYCOL 200POLYETHYLENE TOPICAL; OINTMENT: 57.0% GLYCOL 300 TOPICAL; SOLUTION:29.70% POLYETHYLENE TOPICAL; EMULSION, CREAM: 7.50% GLYCOL 400 TOPICAL;GEL: 45.0% TOPICAL; LOTION: 12.0% TOPICAL; OINTMENT: 65.0% TOPICAL;SOLUTION: 69.90%

Examples of Other Useful Hydrating Agents:

-   Glycolic Acid-   Glycolate salts-   D-panthenol-   Hyaluronic acid-   Lactamide-   monoethanolamine-   Acetamide-   monoethanolamine

Exemplary Permeation Enhancers for Use in the Compositions of theInvention (and Exemplified Amounts Thereof):

Class Excipient FDA Maximum Potency Terpenes MENTHOL TOPICAL LOTION:0.05% LIMONENE, DL- TOPICAL SOLUTION: 0.08% A-TERPINEOL TOPICAL LOTION:10% TOPICAL LOTION: 11% Essential Oils PEPPERMINT OIL TOPICAL OINTMENT:NOT KNOWN Fatty Acids and ISOPROPYL MYRISTATE 0.02%-35% Esters ISOPROPYLPALMITATE 1.8%-3.9% OLEIC ACID TOPICAL SOLUTION: 7.4% OLEYL OLEATETOPICAL OINTMENT: 2.55% STEARIC ACID TOPICAL; CREAM, AUGMENTED: 3.0%TOPICAL; EMULSION, CREAM: 22.60% TOPICAL; LOTION: 20.0% TOPICAL;OINTMENT: 15.0% TOPICAL; SUSPENSION: 1.75% ETHYL ACETATE TOPICAL;SOLUTION: 31.0% DIETHYL SEBACATE TOPICAL; SOLUTION: 24.0% Alcohols,Glycols ALCOHOL 1.20-97.50% and glycerides PROPYLENE GLYCOL TRANSDERMALGEL: 6.0% TOPICAL OINTMENT: 38% TOPICAL OINTMENT AUGMENTED: 65.0%TOPICAL LOTION: 59% TOPICAL LOTION AUGMENTED: 30.0% TOPICAL GEL: 98.09%TOPICAL EMULSION CREAM: 71.08% TOPICAL EMULSION LOTION: 47.50% BENZYLALCOHOL TOPICAL; CREAM, AUGMENTED: 1.00% TOPICAL; CREAM, EMULSION,SUSTAINED RELEASE: 1.0% TOPICAL; EMULSION, CREAM: 2.70% TOPICAL; GEL:50.0% TOPICAL; LOTION: 1.30% TOPICAL; OINTMENT: 2.20% TOPICAL; SOLUTION:2.0% TOPICAL; SUSPENSION: 1.0% CAPRYLIC/CAPRIC TOPICAL; CREAM, EMULSION,TRIGLYCERIDE SUSTAINED RELEASE: PENDING (10.0%) TOPICAL; EMULSION,CREAM: PENDING (10.80%) TOPICAL; SOLUTION: PENDING (50.0%)CAPRYLIC/CAPRIC/STEARIC TOPICAL; OINTMENT: 70.0% TRIGLYCERIDE MYRISTYLALCOHOL TOPICAL; EMULSION, CREAM: 3.0% TOPICAL; LOTION: 1.0% TOPICAL;SUSPENSION: 1.05% CETYL ALCOHOL TOPICAL; CREAM, AUGMENTED: 4.0% TOPICAL;CREAM, EMULSION, SUSTAINED RELEASE: 6.0% TOPICAL; EMULSION, AEROSOLFOAM: 3.22% TOPICAL; EMULSION, CREAM: 12.0% TOPICAL; LOTION: 68.40%TOPICAL; OINTMENT: 7.0% TOPICAL; SUSPENSION: 2.01% CETOSTEARYL ALCOHOLTOPICAL; CREAM, AUGMENTED: 8.0% TOPICAL; EMULSION, CREAM: 12.0% TOPICAL;EMULSION, LOTION: 5.0% TOPICAL; LOTION: 4.0% TOPICAL; OINTMENT: 1.20%TOPICAL; SUSPENSION: 2.50% STEARYL ALCOHOL TOPICAL; AEROSOL: 0.53%TOPICAL; CREAM, AUGMENTED: 4.0% TOPICAL; CREAM, EMULSION, SUSTAINEDRELEASE: 3.0% TOPICAL; EMULSION, AEROSOL FOAM: 0.53% TOPICAL; EMULSION,CREAM: 30.0% TOPICAL; LOTION: 12.0% TOPICAL; OINTMENT: 8.0% TOPICAL;SUSPENSION: 2.01% VAGINAL; EMULSION, CREAM: 42.50% TOPICAL; OINTMENT:PENDING (0.75%) OLEYL ALCOHOL TOPICAL; EMULSION, CREAM: 10.0% TOPICAL;OINTMENT: 5.0% Surfactants SODIUM LAURYL SULFATE TOPICAL; EMULSION,CREAM: 2.50% TOPICAL; LOTION: 0.50% TOPICAL; OINTMENT: 1.0% POLYSORBATE20 TOPICAL; EMULSION: 2.0% TOPICAL; EMULSION, CREAM: 0.80% TOPICAL;LOTION: 7.8% TOPICAL; SOLUTION: 15.0% POLYSORBATE 60 TOPICAL; EMULSION,AEROSOL FOAM: 0.42% TOPICAL; EMULSION, CREAM: 8.0% TOPICAL; LOTION: 5.0%TOPICAL; SHAMPOO: 15.0% TOPICAL; SUSPENSION: 2.85% LECITHIN TOPICAL;GEL: 1.0% TOPICAL; SOLUTION: 1.40%

Other Permeation Enhancers

Class Excipient Terpenes Eucalyptol: 1,8-cineole α-pinene MenthoneNerolidol Terpineol Carvol Carvone Pulegone cyclohexane oxide limoneneoxide Anise Essential Oils Eucalyptus turpentine oil Amides UreaDimethylacetamide (DMA) Diethyltoluamide dimethylformamide (DMF)Dimethyloctamide Dimethyldecamide N-methyl-2-pyrrolidone (NMP)2-pyrrolidone N-dodceyl-2-pyrrolidone (2-pyrrolidone derivative) Fattyacid esters of N-(2-hydroxyethyl)-2- pyrrolidone (HEP)1-butyl-3-dodecyl-2-pyrrolidone 1-ethyl-2-pyrrolidone1-butyl-2-pyrrolidone 1-hexyl-2-pyrrolidone 1-octyl-2-pyrrolidone1-lauryl-2-pyrrolidone 1-methyl-4-carboxy-2-pyrrolidone1-hexyl-4-carboxy-2-pyrrolidone 1-lauryl-4-carboxy-2-pyrrolidone1-methyl-4-methoxycarbonyl-2-pyrrolidone1-hexyl-4-methoxycarbonyl-2-pyrrolidone1-lauryl-4-methoxycarbonyl-2-pyrrolidone N-cyclohexylpyrrolidoneN-dimethylaminopropyl-pyrrolidone N-cocoalkypyrrolidonen-tallowalkylpyrrolidone Fatty Acids and Linoleic Acid Esters SodiumOleate Lauric Acid Capric Acid Neodecanoic acid Fatty acid extract ofcod liver oil Valeric Heptanoic Pelagonic caproic capric caprylicpalmitoleic acid Isovaleric Neopentanoic Neoheptanoic Neononanoictrimethyl hexanoic Neodecanoic Isostearic isopropyl n-butyrate isopropyln-hexanoate isopropyl n-decanoate isopropyl myristate isopropylpalmitate octyldodecyl myristate ethyl acetate butyl acetate methylacetate Methylvalerate Methylpropionate diethyl sebacate ethyl oleateSulfoxides and Dimethyl sulfoxide (DMSO) Similar Decylmethyl sulfoxide(DCMS) Compounds Various N,N-dimethylamides N,N-dimethylformamideDimethylacetamide (DMA) N,N-dimethyloctanamide N,N-dimethyldecanamideAlcohols, Glycols n-alkanols (1-nonanol, octyl alcohol) and GlyceridesLauryl alcohol Propanol Butanol 2-butanol Pentanol 2-pentanol HexanolOctanol Nonanol Decanol glycerol monocaprylate decyl alcohol Laurylalcohol Linoleyl alcohol linolenyl alcohol ethylene glycol diethyleneglycol triethylene glycol dipropylene glycol Propanediol ButanediolPentanediol Surfactants Sodium laurate sodium octyl sulfatecetyltrimethylammonium bromide tetradecyltrimethylammonium bromideoctyltrimethyl ammonium bromide benzalkonium chloride cetylpyridiniumchloride dodecyltrimethylammonium chloride hexadecyltrimethylammoniumchloride hexadecyl trimethyl ammoniopropane sulfonate oleyl betaineCocamidopropyl Hydroxysultaine cocamidopropyl betaine Brij (30, 93, 96,99) Span (20, 40, 60, 80, 85) Tween (20, 40, 60, 80) Myrj (45, 51, 52)Miglyol 840 sodium cholate sodium salts of taurocholic (TC) Glycolicdesoxycholic acids Phospholipids phosphatidyl glycerol phosphatidylglycerol derivatives (PGE, PGS, DMPG, DSPG, DOPG) phosphatidyl cholinederviatives (PCS, PCE, DOPC, DLPC, HPC) Cyclodextrin β-cyclodextrinComplexes methyl-β-cyclodextrin O-carboxymethyl-o-ethyl-B-cyclodextrin(CME- B-CD) 2-hydroxypropyl-β-cyclodextrin (HPβCD)2,6-dimethyl-β-cyclodextriin (DIMEB) Amino Acid N-dodecyl-L-amino acidmethyl ester Derivatives n-pentyl-N-acetyl prolinate esters of omegaamino acids (octyl-6- aminohexanoate and decyl-6-aminohexanoate) OthersClofibric Acid (amide and esters of) Enzymes (phopholipase C,triacylglycerol hydrolase (TGH, phospholipase A2

In certain embodiments of the invention where administration of morethan one therapeutic agent or drug is desired, the different therapeuticagents or drugs can be separately applied to one or both upper eyelids(or to the same region of the skin in the case of transdedrmalapplication or to the same eye in the case of eye drops and the like forapplication to the underside of the eyelid(s)) or the differenttherapeutic agents or drugs may be applied to different eyelids (ordifferent regions of the skin in the case of topical transdermalapplication or different eyes in the case of eye drops and the like forapplication to the underside of the eyelid(s)). In other embodiments ofthis aspect of the invention, one composition containing therapeuticagent or drug and up to 1 wt % or more of a muscle fasciculating agentand optional ingredients such as vasodilator, vasoconstrictor,permeating agent and combinations thereof is applied to the first eyelidof a human patient, while the second composition, which is applied tothe other eyelid, does not contain a micro fasciculating agent and/orone or more optional component. For example, combination therapy forglaucoma or dry eye where two or more active agents are used to treatthe condition may be carried out by applying one drug or set of drugs toone eyelid and another drug or combination of drugs to the other eyelid.Similarly, one therapeutic component such as a vasodilator may beapplied to one eyelid and other active components and other componentsmay be applied to the other eyelid. It is understood that the sametreatments apply to eyedrops and the like that are applied to the eyeand which have contact with the underside of the eyelid(s).

For delivery of certain drugs or therapeutic agents or for treatment ofcertain conditions or diseases it may be desirable to administer thecomposition of the invention via injection of a solution containing thedesired drug or therapeutic agent directly into the underside of anyportion of the eyelid, such as that portion of the eyelid in directcontact with the eye although contact with the eye is not necessary,rather than by topical application to the upper eyelid. This method ofdrug delivery is most useful for accessing the periocular space andtissues to (a) achieve a high loading dose of drug; and (b) overcomedrug permeability due to drug characteristics such as high molecularweight, ionization, etc. and is less invasive to the patient thaninjecting under the conjunctiva around the eyeball. For example, a highdose of Triamcinolone (Kenalog) MW 434 Daltons, a long acting steroid,or Avastin, a large charged molecule MW 149,000 Daltons can be injectedvia this method in order to achieve high drug concentrations without theinvasive injection into or adjacent to the eyeball which most patientsfind unappealing and traumatic. Also, a therapy regiment may be appliedwhen warranted, which includes an initial injection of a composition ofthe invention into the underside of the eyelid, followed by applicationof a topical composition containing a therapeutically effective amountof the therapeutic agent(s) to at least one eyelid at appropriate timeintervals, e.g., within 1 to 24 hours following the injection and onceper day thereafter until the condition is effectively treated orcontrolled. Conditions that can be treated in this manner include butare not limited to keratitis inflammation such as iritis, bleedingconditions such as hyphema, vascular occlusions, retinal edema, agerelated macular degeneration, and diabetic retinopathy. This method canbe also be used to deliver steroids or antibiotics to the eye forexample.

In another embodiment of the invention, iontophoresis is employed toensure faster and possibly more effective uptake of drug or therapeuticagent into the eyelid or skin and hence circulatory system. Use ofiontophoresis to deliver a composition optionally containing a microfasciculating agent and drug or therapeutic agent can result in fasteruptake and sustained release of drug or therapeutic agent. In thisaspect of the invention, the drug that is applied to the skin or uppereyelid surface via iontophoresis is charged, e.g., Avastin (bevacizumab)which is a large charged molecule of MW 149,000 which ensures that itcan be driven across the eyelid skin via the low electrical currentprovided by the iontophoresis electrode.

Although the inventors do not wish to be bound by any theory, it isproposed that the present methods and compositions achieve sustainedrelease of therapeutic agent from the discovery of the uniquelypermeable and vascular skin of the human eyelid into the systemic bloodflow as long as the therapeutic agent remains unbound within the skinlayer of the upper eyelid. Further, in those compositions of theinvention containing a muscle fasciculating agent, it is believed thatcontinual microcontractions in the blink muscle of the eyelid and musclesurrounding the eyeball caused by the muscle fasciculating agent resultin a continual pumping action moving the drug into the surroundingmuscle and the vascular system, which in humans flows towards theeyeball rather than away (as in other mammals), which in turn,facilitates penetration of the drug into the posterior segments of theeye (e.g., lens, vitreous, cilliary body, pars plana and plicata,retina, optic nerve, choroid and sclera as well as into the vascularsystem in general. As a result of the pumping action achieved throughthe use of a muscle fasciculating agent, or in various combinations withvasodilators, vasoconstrictors, and/or manipulation of the pH of thecompositions of the present invention, the present methods enable theuse of lower concentrations of therapeutic agent in topical formulationsto treat conditions in the eye previously treated by systemic, oral orother topical routes using higher concentrations of drug or therapeuticagent than required by the present methods. The present invention alsoenables reduced frequency of treatment, improved drug targeting,continuous drug delivery, patient convenience and ease of treatment andpotentially enhanced therapeutic effects.

Similarly, when the composition is applied to the skin rather than tothe outer surface or underside of the eyelid(s), continualmicrocontractions in the muscle surrounding the area to which thecomposition is applied caused by the muscle fasciculating agent resultin a continual pumping action moving the drug into the surroundingmuscle and the vascular system. By manipulating the amount of a microfasciculating agent in the compositions of the invention, it is possibleto direct the drug in therapeutically effective amounts to its propertarget and in some cases to a target that previously has not beenaccessible by non-invasive means or in concentrations not previouslyobtained via topical administration. By utilizing the unique vascularand dermal characteristics of the upper eyelid and optionally, inclusionof a micro fasciculating agent in the compositions, it is possible tospecifically target and deliver drugs that heretofore could not betopically administered to achieve therapeutic concentrations of drug atthe target site, such as large molecules, e.g. certainanti-inflammatories and antibiotics, lipophilic molecules, hormones,immunosuppressive agents, chemotherapeutic agents, non-steroidalanti-inflammatory agents, and anti-allergy agents. Antibiotics such astetracyclines and other drugs such as demarcarium bromide,physiostigmine, neostigmine, pyridostigimine, isofluorophate,diisopropylfluorophosphate, carbachol, dipivefrin, apraclonodne,isoproternol, bromocriptine, phenylephrine, and echothiophate iodide,are non-limiting examples of drugs that can be delivered via thecompositions, kits and methods of the invention. The skilledpractitioner will appreciate that any therapeutic agent or drug (orcombination of agents/drugs), particularly those having a size range of6000 Daltons or smaller may be included in the compositions and kits ofthe invention, although larger molecules may also be used, e.g.,cyclosporine, botox and other large organic molecules, and administeredaccording to the methods described herein to achieve therapeuticconcentration at the desired target site. Nonlimiting examples of activeagents that may be delivered by the methods and compositions of theinvention include glaucoma agents such as Ophthalmic Beta-Blockers,Carbonic Anhydrase Inhibitors, Alpha-Agonists, Miotics, Prostaglandinanalogs, Latanoprost; Brimatoprosost; Acetazolamide; Apralonidine;Betaxolol; Brimonidine; Brinzolamide; Carbachol; Carteolol; Dorzolamide;Dipivefrin; Epinephrine; Levobunolol; Metipranolol; Methazolamide;Pilocarpine; Timolol; and Travaprost; Dry Eye agents such asCyclosporine; Allergy Agents; Antihistamines;Antihistamine/decongestants; Antihistamine/mast cell stabilizers;Corticosteroids; Decongestants; Homeopathics; Mast cell stabilizers;Non-steroidal anti-inflammatory drug such as Optivar/Azelastine;aphazoline; Oxymetazoline; Phenylephrine; Tetrahydrozoline;Emandine/Emedastine; Elestat/Epinastine; Pataday, Patanol/Olopatadine;Levocabastine; Alomide/Lodoxamide; Cromolyn; Alaway/Zaditor/Ketotifen;Alocril/Nedocromil; Alamast/Pemirolast; Loratadine and Pseudoephedrine;antibiotics such as Ciprofloxacin; Gatifloxacin; Gentamicin;Levofloxacin; Moxifloxacin; Ofloxacin; Sulfacetamide; Tobramycin;steroids such as Dexamethasone; Fluorometholone; Loteprednol; Medrysone;Prednisolone; Rimexolone; andnon-steroidal anti-inflammatory agents suchas Bromfenac; Diclofenac; Flurbiprofen; Ketorolac; and Nepafenac.

Topical administration of the compositions of the invention to the uppereyelid can be achieved by any known means such as for example, throughthe use of an applicator such as a patch containing the composition onits surface intended for contact with the upper eyelid; a rollerballapplicator integrally connected to a container in which the inventioncomposition is contained; an applicator strip or plaster comprising acomposition of the invention on the surface to be applied to the eyelid;a pliable finger cot containing a composition of the invention as ablister positioned on the tip thereof; or an applicator for dipping intoa solution of a composition of the invention, any of which may beprovided in a kit for a patients' or physician's or other medicalpersonnel's use.

Topical administration of the compositions of the invention to anyregion of the skin is achieved by any known means, for example, byapplication of a patch containing the composition on a portion of itssurface that is applied to the skin, a cream or lotion, strip, rollerball and the like.

Kits containing a composition(s) of the invention may include single usedosage forms of the invention composition, or may include a vialcontaining multiple doses that are to be metered out by the patient orvia the applicator itself. Further, kits may include formulations ofdifferent therapeutic agents for treatment of the applicable conditionor disease, intended to be applied to different eyelids or areas of theskin and/or at different times during the treatment regimen. Kits willalso include, when necessary, instructions for the appropriate dosingregimen.

EXAMPLES Example 1 Treatment of Severe Dry Eye

Two human patients with preexisting symptomatic severe dry eye weretreated as follows. The dry eye condition was assessed by the Schirmerstear test and corneal observations. Each subject received a singleapplication of a lotion containing 1% of pilocarpine and 0.16% caffeineapplied to the upper eyelid of the more severely affected eye by directapplication of the lotion to the upper eyelid. The effect of treatmentwas then measured over six hours in regards to tear production andcomfort level of the patient.

There was a rapid increase in tear production in both affected eyes inboth subjects. There was an exponential increase in tear production inboth patients within one hour of application that was sustained for sixhours, as can be seen in FIG. 2.

Prior to treatment both patients ranked their comfort level of theaffected eye as 0 on a scale of 0 to 4 with 0 being the most irritatedand 4 being the most comfortable. After application of pilocarpine, bothpatients reported a “cooling” feeling in the affected eye within thirtyminutes of treatment, which was sustained for six to eight hours and acomfort level of 4 was achieved and maintained within two hours oftreatment. A plot of the patients' comfort level is shown in FIG. 3.

Example 2 Intraocular Pressure

A normal human subject was selected to determine the effects of a singleapplication of percutaneous upper eyelid application of a cream/lotioncontaining 0.2% timolol and 0.16% caffeine to the outer surface skin ofone upper eyelid. The intraocular pressure was recorded in both thetreated and untreated eye both before and after application of thecomposition. Additionally, the subject's vital signs, including pulserate and blood pressure were recorded at the same time intervals as eyepressure was recorded. The effect of treatment was measured for overfifty two hours.

After a single application of timolol to one eyelid there was a rapiddecline in intraocular pressure in both eyes as shown in FIG. 4. Thetreated eye showed a 73% drop in intraocular pressure within four hoursof treatment, which returned to baseline eye pressure within 52 hours.The untreated eye rapidly dropped intraocular pressure by 50% within thesame time frame as the treated eye, demonstrating the systemicabsorption of timolol. The intraocular pressure of the untreated eyeremained depressed for 52 hours, just as with the treated eye.

Although the timolol was absorbed systemically to reach the untreatedeye, the subject's vital signs showed stability within 0.04% for heartrate and 0.5% change for systolic pressure, as shown in FIG. 5.

Example 3 Effects of Topical Application of Physostigmine to One Eyelid

A normal human subject was selected to determine the effects of a singleapplication of percutaneous upper eyelid application of a cream/lotioncontaining 5% physostigmine, a parasympathetic agonist, 0.16% caffeineto the outer surface skin of one upper eyelid. The effects on tearproduction, intraocular pressure and pupilary constriction were measuredin both the treated and untreated eye both before and after applicationof the composition. Additionally, the subject's vital signs, includingpulse rate and blood pressure were recorded at the same time intervalsas eye pressure was recorded. The effect of treatment was measured forover twelve hours. Prior to treatment, the treated eye showed a drynesslevel of 0, while the untreated eye had a dryness level of 2 mm bySchirmers measurement.

After a single application of physostigmine to one eyelid there was arapid increase in tear production from 0 to 5 mm in the treated eye bySchirmers measurement which declined over a period of 12 hours, as shownin FIG. 6. Tear production in the untreated eye remained unchanged overthe same time period. The treated eye showed a 50% drop in intraocularpressure within an hour of treatment, which returned to baseline levelwithin 12 hours. The intraocular pressure of the untreated eye remainedunchanged over the testing period. These results are shown in FIG. 7.

The pupil of the treated eye rapidly became miotic (pinpoint pupil),while the pupil of the untreated eye increased in size, as shown in FIG.8. The increase in pupil size in the untreated eye is the result of asystemic reaction—due to the systemic parasympathetic stimulation by asingle physostigmine application, there was an increased sympatheticresponse to maintain the vital signs and normal cardiac output,resulting in pupilary dilation in the untreated eye.

The systemic effects of application of physostigmine to one eyelidincluded an initial rapid decline in heart rate of 16% compared tobaseline in the same time frame as the ocular effects. Physostigmineinduced bradycaria in the subject, which was matched by a 15.7% increasein systolic blood pressure. The systemic effects are shown in FIGS. 9and 10.

Example 4 Effect of Topical Application of Latanoprost to One Eyelid

A normal human subject was selected to determine the effects of a singlepercutaneous application to one upper eyelid of a cream/lotioncontaining 0.025% latanoprost, and 0.16% caffeine (applied to the outersurface skin of the upper eyelid). The effects on intraocular pressurewere measured in both the treated and untreated eye both before andafter application of the composition and were measured at intervals forthree months. The results are shown in FIG. 11.

FIG. 11 shows the decline in human intraocular pressure after a singleapplication with transdermal latanoprost on the skin of one eyelid only.The treated eye showed a 53.8% drop in intraocular pressure in 10 hoursand had not returned to pre-treatment levels over the three monthobservation period. The subject's intraocular pressure remained at 9 orbelow in the treated eye.

The untreated eye also dropped intraocular pressure by 36.3% within thesame time frame and had not returned to baseline level after threemonths of observation. The subject's intraocular pressure remained at 10or below in the untreated eye. The mechanism for this rapid decline inpressure in the untreated contralateral eye is by the pharmacologicalactivity of latanoprost via systemic absorption.

Latanoprost is known to increase uveoscleral outflow by increasingscleral permability. These results demonstrate a significant sustainedintraocular pressure reduction after a single transdermal application toone eyelid that is unknown in ophthalmology even with regular daily eyedrop therapy and is probably due to a long lasting increase in scleralpermability bilaterally. These results demonstrate that the presentinvention can be applied to treatment of the entire sclera of the eye asopposed to traditional treatment which treats only a small portion ofthe sclera which is accessible via the anterior segment of the eye.

The treated eye demonstrates a greater sustained drop in intraocularpressure than the untreated eye. The probable mechanism for this effectis the direct penetration of latanoprost to the posterior segment of thetreated eye to change the outflow of the sclera in addition to thesystemic blood flow carrying the drug to the treated eye and theuntreated eye. The untreated eye demonstrates the effect achieved solelyby systemic transport of latanoprost to the eyeball.

Example 5 Effect of Topical Application of Brimonidine to One Eyelid

A normal human subject was selected to demonstrate the effect of asingle application of transdermal 0.05% Brimonidine lotion/cream withoutcaffeine to the unaltered, untreated skin of the upper eyelid of oneeye. The results are shown in FIG. 12. The intraocular pressure in boththe treated and untreated eyes remains virtually unchanged over a periodof seven hours and actually increased in the treated eye by one point.

The same treatment was then repeated in the same subject usingtransdermal application to a single eyelid of a lotion/cream compositioncomprising 0.05% Brimonidine and 0.16% caffeine. The results are shownin FIG. 13. The intraocular pressure decreased symmetrically in botheyes by 25% within one hour after application and by 37.5% in thetreated eye and 31.3% in the untreated eye in two hours. The effect of asingle application to one eyelid was sustained in both eyes 28 hourslater and was 31.3% less than baseline in both eyes. The effect lastedfor two weeks and gradually wore off in 4 weeks. The graph shows thefirst 48 hours of this period.

Brimonidine is routinely administered as an eye drop which is typicallydosed at least two times a day and produces about a 24% drop inintraocular pressure, with numerous well known side-effects per FDA dataincluding itching, redness, and intolerance in up to 20% of patientsnecessitating stoppage of the drug. Additionally, according to FDAclinical data, 30% more patients had to discontinue the Brimonidine 0.2%eye drop use due to lack of clinical effect. In contrast, the resultsherein show a dramatic clinical effect without any side effects usingonly 25% of the concentration of the drug that the FDA tested.

Example 6 Topical Eyelid Application of Insulin/Humulin to aNon-Diabetic Subject

A normal non-diabetic human subject was selected to demonstrate theeffect of a single transdermal application of a lotion/cream containing4 units of Insulin/Humulin and 0.16% caffeine to the unaltered,untreated normal skin of both upper eyelids. The results are shown inFIG. 14.

The subject's starting glucose level dropped by 12.5% in 45 minutes, and15.6% in 1 hour and 15 minutes. The subject's blood sugar remained lowat 81 and the subject reported hypoglycemic symptoms of sweating,tachycardia, dizziness, and headache. Consequently, the study wasaborted and glucose was administered.

Example 7 Topical Eyelid Application of Insulin/Humulin to a DiabeticSubject

A non-insulin dependent diabetic human subject was selected todemonstrate the effect of a single transdermal application of alotion/cream comprising 4 units Insulin/Humulin and 0.16% caffeine tothe unaltered, untreated normal skin of a both upper eyelids of botheyes. All diabetic medications had been discontinued for 3 days prior toachieve systemic washout of oral medications. The results are shown inFIG. 15.

FIG. 15 shows the results of three trials: one trial was conducted with4 units of Humulin and two trials were conducted with 4 units ofHumulog. Humulog is insulin lispro which is a rapid and intermediateacting insulin of MW 5808 Daltons while Humulin is MW 5807.72 Daltonsand is short acting.

In Trial I (Humulin) the subject's blood sugar dropped by 18.1% in 2hours, 44.6% in 3.5 hours, and 49% in 5.5 hours to a normal range ofblood glucose level.

In Trial II (Humulog), the subject's blood sugar response showed a moreprecipitous response with blood sugar decline of 45.4% in a 3.5 hourperiod despite a higher starting blood glucose level compared to Trial 1of Humulin. Finally, Trial I of Humulog was also conducted todemonstrate the effect of Humulog at an even higher starting bloodglucose level of 351 mg/dl. The subject's blood sugar dropped by 57.8%in 2.5 hours, and by 65.6% to a normal level of 121 in 4.5 hours.

These results demonstrate clinical effectiveness of the presentinvention at three different levels of diabetic range blood glucoselevels in a human diabetic patient.

Example 8 Topical Eyelid Application of Lisinopril

An uncontrolled hypertensive human subject was selected to demonstratethe effect of a single transdermal application of a cream/lotioncomposition comprising 8 mg lisinopril and 0.16% caffeine to theunaltered, untreated normal skin of the upper eyelids of both eyes ofthe subject. All hypertensive medication (Telmisartan) had beendiscontinued for 10 days prior to achieve systemic washout. Thepatient's baseline blood pressures off all hypertensive medications werechecked a total of 10 times on different days and times of the day. Theblood pressure averaged a systolic of 145 and a diastolic of 85.

The subject's blood pressure was re-measured immediately prior toapplying the lisinopril/caffeine transdermal cream and was 140 systolicand 80 diastolic. The systolic blood pressure sustained a 15.7% drop inthe first hour post application with the diastolic pressure remainingstable. Within two hours the systolic blood pressure declined further to17.8% lower than baseline and the diastolic blood pressure for the firsttime, now declined by 12.5%. For the next 26 hours, the systolic bloodpressure ranged from a drop of 11.4% to 17.1% less than baseline. Thediastolic blood pressure also remained less than baseline and rangedfrom 5% to 12.5% less than baseline pre treatment diastolic bloodpressure. Even 52 hours after application, the subject's blood pressurewas 115 systolic and 73 diastolic, which represents a 17.8% drop insystolic blood pressure and an 8.75% drop in diastolic blood pressurecompared to pretreatment blood pressure. These results are shown in FIG.16.

The subject's heart rate during the trial showed a 16.6% increase duringthe first two hours of the trial during which time both the systolic anddiastolic blood pressure declined by 17.8% and 12.5%, respectively. Thepercentage rise in heart rate nearly matches the percentage decline insystolic blood pressure, demonstrating the human body's ability tomaintain perfusion by compensating for a pharmacologically induceddecline in blood pressure (hypotension) by increasing heart rate viaendogenous sympathetic compensatory mechanisms. This increase in heartrate is not sustained, since the patient's endogenous mechanisms toincrease vascular resistance were probably activated leading to asubsequent increase in systolic blood pressure to 14.3% less thanbaseline and the heart rate went back to baseline. The diastolic bloodpressure remained stable, but did not affect the heart rate as did thesystolic blood pressure.

Example 9 Topical Eyelid Application of Pilocarpine

A human subject with preexisting symptomatic severe dry eye was selectedfor testing. The dry eye was quantified by Schirmer's tear testing andcorneal findings. The subject received treatment with a singleapplication of a cream/lotion comprising 1% pilocarpine without caffeineto the normal untreated, unaltered skin of one upper eyelid. The effectof treatment was then measured over six hours in tear production andcomfort. The results are presented in FIGS. 17 and 18 and are describedbelow.

FIG. 17 demonstrates the rapid increase in human tear production in thesetting of severe dry eye in a subject who was treated with a singletransdermal application of pilocarpine lotion as described above. Thetreatment had been applied to the upper eyelid skin of the eye with abaseline tear production of zero. The subject showed an exponentialincrease in natural tear production within an hour; the increase wasself sustained for six hours. Although the tear production wassignificant, it is somewhat less than that generated by the applicationof a combination of pilocarpine and caffeine (shown in FIG. 2).

There was also an increase in tear production in the untreated eye,which though severely dry also was not as bad as the baseline in thetreated eye. The level of tear production in this eye approached normalafter treatment.

FIG. 18 shows the subjective comfort level of the severe dry eye subjectfor the treated and untreated eye both before and after application ofpilocarpine lotion/cream. Prior to treatment, the comfort level of thedry eye was ranked on a scale of 0 to 4; 0 being the most irritated and4 being the most comfortable. After application of Pilocarpinelotion/cream, the subject reported an increase in comfort level to aconstant score of three. However, the subject noted the absence of the“cooling” feeling with this treatment.

Example 9 Formulations

Each of the following formulations were made by the same basicformulation procedure:

-   1) In the main tank, added water, and BG Glycerin. Mixer was turned    on and brought to medium speed.-   2) Carbopol 940 was slowly sprinkled into the vortex. Continued    mixing for 15-20 minutes until free of clumps.-   3) Heated the mixture to 65 C and added phase C (preservatives)-   4) In a separate mixing hot tank, the oil phase (Phase D) was    combined and heated to 65° C.-   5) When the main tank and premix tank reached 65° C., the oil phase    was added to the main tank.-   6) PEG 8 and optionally caffeine were added with continued mixing it    until coos down to 50° C.-   7) In separate bucket, a 25% sodium hydroxidesolution was prepared    with deionized water, mixing until sodium hydroxide dissolved.    (Cautious: Be sure to wear sleeve, lab coat and safety goggles when    preparing this solution)-   8) The sodium hydroide solution was poured into the main batch.    Mixing speed was turned to high speed until a slight vortex was    achieved.-   9) The batch was cooled to 40-50° C. and then Tetrasodium EDTA was    added and mixed for 5-10 minutes.-   10) Add Saccharide Isomerate and mix until the batch is homogenous.-   11) A top and bottom sample were obtained for analysis.-   12) Mixed in the listed drug or therapeutic agent, partially    dehydrated into 0.005 gm of the formulation.    The following are representative examples of gel, cream, ointment    and vesicle based topical bases used in the examples set forth    above.    A. Gel

Excipient Use Hydroxyethylcellulose Viscosity modifier EthanolPermeation enhancer Methyl paraben Preservative Propyl parabenPreservative Water/BufferB. Cream

Excipient Use Stearic acid Oily phase Propylene glycol monostearateEmulsifier Propylene glycol Humectant Isopropyl palmitate/Isopropylmyristate Permeation enhancer Polysorbate 60 Emulsifier Methyl parabenPreservative Propyl paraben Preservative Water/BufferC. Ointment

Excipient Use White petrolatum Oily phase White wax Oily phase Stearylalcohol Emulsifier Cholesterol Emulsifier Isopropyl palmitate/Isopropylmyristate Permeation enhancerD. Ethosomes (Vesicular Technology)

Excipient Use Distearyl phosohotidyl choline Vesicle forming agentEthanol Skin permeation enhancer Cholesterol Vesicle membrane stabilizerCarbopol Gel forming agent WaterFormulations Used in the Examples:Pilocarpine 1% Formulation Without Caffeine

Phase Ingredients % by WT A Water (Deionized) 65.7000 D Caprylic/capricTriglyceride 15.6500 D C12-20 Acid PEG-8 Ester 5.0000 A Butylene Glycol4.4400 A Glycerin 3.2500 H Saccharide Isomerate 2.0000 E PEG-8 1.75 DCetyl Alcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F SodiumHydroxide (25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05Pilocarpine 1% Formulation with 0.16% Caffeine

Phase Ingredients % by WT A Water (Deionized) 65.7000 D Caprylic/capricTriglyceride 15.6500 D C12-20 Acid PEG-8 Ester 5.0000 A Butylene Glycol4.4400 A Glycerin 3.2500 H Saccharide Isomerate 2.0000 E PEG-8 1.75 DCetyl Alcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F SodiumHydroxide (25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05 ECaffeine 0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsPhysostigmine (5%) Formulation with Caffeine

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05 E Caffeine0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsTimolol (0.25%) Formulation with Caffeine

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05 E Caffeine0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsLisinopril Formulation

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05 E Caffeine0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsLatanoprost Formulation without Caffeine

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsLatanoprost Formulation with Caffeine

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05 E Caffeine0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cps

Brmonidine (Alphagan P) Formulation With CaffeinePhase Ingredients % byWT A Water (Deionized) 657000 D Caprylic/capric Triglyceride 156500 DC12-20 Acid PEG-8 Ester 50000 A Butylene Glycol 44400 A Glycerin 32500 HSaccharide Isomerate 20000 E PEG-8 1.75 D Cetyl Alcohol 1 B Carbomer 9400.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide (25% 0.3 Solution) CMethylparaben 0.2 C Propylparben 0.05 E Caffeine 0.16

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cpsBrimonidine (Alphagan P) Formulation without Caffeine

Phase Ingredients % by WT A Water (Deionized) 657000 D Caprylic/capricTriglyceride 156500 D C12-20 Acid PEG-8 Ester 50000 A Butylene Glycol44400 A Glycerin 32500 H Saccharide Isomerate 20000 E PEG-8 1.75 D CetylAlcohol 1 B Carbomer 940 0.3 G Tetrasodium EDTA 0.2 F Sodium Hydroxide(25% 0.3 Solution) C Methylparaben 0.2 C Propylparben 0.05

PROPOSED TEST SPECIFICATION Appearance White Viscous Solution ColorWhite Viscous Solution Order Fragrance Free Clarity Opaque pH 5.7-6.7 %solids 25.7-28.5 Viscosity 57,000-96,000 cps

What is claimed is:
 1. A method for treating an ophthalmic condition ofthe surface or interior of the eyeball or an ocular gland in a humanpatient in need thereof comprising topically administering a compositionto the outer surface of at least one upper eyelid of the patient, saidcomposition comprising (1) a therapeutically effective amount of atleast one therapeutic agent effective for treatment of the ophthalmiccondition, (2) from 0.001% to 50 wt % of a muscle fasciculating agentselected from the group consisting of caffeine, theobromine,theophylline and pentoxifyline and (3) a pharmaceutically acceptablecarrier, wherein said therapeutic agent is selected from the groupconsisting of anti-glaucoma agents, vasoconstrictors, vasodilators,anticholinergic agents, cholinergic agents, α-agonists, β-agonists,anti-inflammatories, secretogues, antibiotics, mast cell stabilizers andcombinations thereof, wherein said administration results in delivery ofthe therapeutic agent across the eyelid and to target tissue of theeyeball or ocular gland.
 2. The method of claim 1 wherein thecomposition is applied to one upper eyelid of the patient.
 3. The methodof claim 1 wherein the therapeutic agent is a vasoconstrictor.
 4. Themethod of claim 3 wherein the vasoconstrictor is applied to theperimeter of the outer surface of at least one eyelid of the patient. 5.The method of claim 1 wherein a vasodilator is the sole activetherapeutic agent applied to the at least one eyelid of the patient. 6.The method of claim 1 wherein the composition further comprises apenetrating agent.
 7. The method of claim 1 wherein the musclefasciculating agent is caffeine.
 8. The method of claim 7 wherein thecomposition comprises from 10 mg to 500 mg caffeine.
 9. The method ofclaim 1 wherein the ophthalmic condition is glaucoma and wherein the atleast one therapeutic agent is a secretogue selected from the groupconsisting of timolol, brimonidine and latanoprost, and the musclefasciculating agent is caffeine.
 10. The method of claim 1 wherein theophthalmic condition is dry eye and wherein the at least one therapeuticagent is pilocarpine and the muscle fasciculating agent is caffeine. 11.The method of claim 1 wherein the composition further comprises anionotropic agent.
 12. The method of claim 1 wherein the therapeuticagent comprises a combination of a vasodilator and a vasoconstrictor.13. The method of claim 1 wherein the composition is applied to theouter surface of at least one eyelid in the form of a gel, lotion,cream, spray, foam, adhesive formulation, plaster, film, strip, poulticeor ointment.
 14. The method of claim 1 wherein application of thecomposition to the outer surface of at least one eyelid results indelivery of the therapeutic agent to the posterior segment of theeyeball.
 15. The method of claim 1 wherein application of thecomposition to the outer surface of one eyelid results in delivery ofthe therapeutic agent to the contralateral eye.
 16. The method of claim1 wherein the ophthalmic condition is seasonal allergy or allergic eyedisease.
 17. The method of claim 1 wherein said administration resultsin sustained release of the at least one therapeutic agent into theeyeball or ocular gland or on the surface of the eyeball.
 18. The methodof claim 1 wherein the composition further comprises a permeating agent.19. A method of treating an ophthalmic condition of the surface orinterior of the eyeball or an ocular gland in a human patient in needthereof comprising applying to the outer surface of at least one eyelidof the patient a first composition comprising (1) a therapeuticallyeffective amount of a first therapeutic agent for treatment of theophthalmic condition, (2) from 0.001% to 50 wt % of a musclefasciculating agent selected from the group consisting of caffeine,theobromine, theophylline and pentoxifyline, and (3) a pharmaceuticallyacceptable carrier; and applying to the outer surface of at least oneeyelid a second composition comprising (1) a therapeutically effectiveamount of a second therapeutic agent for treating the ophthalmiccondition, 2) from 0.001% to 50 wt % of a muscle fasciculating agentselected from the group consisting of caffeine, theobromine,theophylline and pentoxifyline, and (3) a pharmaceutically acceptablecarrier; wherein said second therapeutic agent is different from saidfirst therapeutic agent, and wherein administration of said first andsecond compositions results in delivery of each of the first and secondtherapeutic agent across the at least one eyelid and to target tissue ofthe eyeball or ocular gland.
 20. The method of claim 19 wherein both thefirst and second compositions comprise a muscle fasciculating agent. 21.The method of claim 20 wherein the first and second compositions areeach applied to the outer surface of a different eyelid of the patient.22. The method of claim 19 wherein the first composition comprises avasodilator and the second composition comprises a vasoconstrictor. 23.The method of claim 22 wherein the vasodilator and the vasoconstrictorare applied to different regions of the outer surface of the at leastone eyelid.
 24. The method of claim 22 wherein the vasoconstrictor isapplied to the perimeter of the outer surface of the at least oneeyelid.
 25. The method of claim 19 wherein the first composition, secondcomposition or both further comprises an ionotropic agent.